ACS Publications. Most Trusted. Most Cited. Most Read
Quick View

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:Acc. Chem. Res. 2014, 47, 10, 3127-3134
RETURN TO ISSUEPREVArticleNEXT

A Philosophy for CNS Radiotracer Design

View Author Information
† Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States
‡ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
*E-mail: [email protected]
Cite this: Acc. Chem. Res. 2014, 47, 10, 3127–3134
Publication Date (Web):October 1, 2014
https://doi.org/10.1021/ar500233s

Copyright © 2014 American Chemical Society. This publication is licensed under these Terms of Use.

Request reuse permissions
  • Open Access

Article Views

4456

Altmetric

-

Citations

102
LEARN ABOUT THESE METRICS
PDF (2 MB)
Get e-Alerts
SUBJECTS:

Abstract

High Resolution Image
Download MS PowerPoint Slide
Conspectus

Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain.

However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area.

We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers.

In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood–brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible.

Introduction

ARTICLE SECTIONS
Jump To
PET radiotracers are small molecules containing a single positron emitting isotope (e.g., 11C, half-life of 20.38 min, or 18F, half-life of 109.8 min) and are detected in vivo by the measurement of highly tissue-penetrant and coincident γ rays produced upon positron annihilation. Molecular imaging with PET radiotracers can afford a sensitive and relatively noninvasive (1, 2) quantitation of biochemical parameters within a living human, including within the CNS. These characteristics provide PET imaging with immense potential to fill the void of techniques for assessment of neurophysiological biomarkers of healthy and diseased states in living human subjects and patients. (3, 4) Applications of CNS PET imaging include establishing proof-of-mechanism and optimal dosing for novel therapeutic agents, allowing for accelerated decision-making in clinical trials. Despite this potential, only 38 central nervous system targets are currently addressed by PET in humans, (5) while thousands of brain proteins have yet to be explored. (6) This limited availability of CNS PET radiotracers is partly due to the wide range of demanding criteria that must be fulfilled, especially for novel, higher-risk targets, and the empirical nature of radiotracer development. (7)
In this Account, we present a framework of chemical and biological considerations to optimize radiotracer development, with special attention given to radiotracers for novel CNS targets. Figure 1 showcases the components of the development process, which are represented by individual pools of a fountain. Except for well-studied targets previously vetted during drug discovery, the traditional pipeline approach of lead discovery and optimization may not be strategic for radiotracer development. Instead, the entry point into radiotracer development will vary significantly depending on existing knowledge of the biological target. Data collected from each development component will critically inform decision-making in other components, leading to progressive movement between the different tracer development pools. The streams of water connecting each pool represent one example of the cross-component approach we have found to be maximally efficient for PET radiotracer development.

Figure 1

Figure 1. Artistic representation of the radiotracer development process. Blue streams highlight one of many potential pathways for initial radiotracer development, which branches into two pathways after chemical design. Purple streams indicate radiotracer development pathways in which previously explored components are revisited for radiotracer optimization. Drawing used with permission of Aaron Keefe.

High Resolution Image
Download MS PowerPoint Slide

PET Radiotracer Construction

ARTICLE SECTIONS
Jump To

Preface: Biomedical Question Selection

The end goal for CNS radiotracer development is to address a biomedical question by reporting on the neurochemistry of the living human brain. This biomedical question often arises from an unmet clinical need for which PET imaging can improve treatment paradigms or aid diagnosis in patients. However, the potential of PET imaging for CNS-disease diagnosis, while much touted, is currently low. The other main focus of CNS radiotracer development is clinical brain research. In this arena, basic biomedical research beckons for the development of new PET radiotracers for emerging targets or pathways implicated in human disease, wherein radiotracers are used to discover or validate human neurobiological concepts or as a drug development companion. (8-10)
Due to the expensive and time-consuming nature of radiotracer development and the low commercial potential for most radiotracers, we must carefully select our biomedical questions. To identify biomedical questions related to unmet medical needs, recent literature can provide a focus, but it is also crucial to complete “market research”. Specifically, insight from physicians who can comment on medical needs in their practice or in clinical research is invaluable. If imaging with a radiotracer for an unmet clinical need would not be “prescribed”, then there may be no need to develop the radiotracer, particularly diagnostic radiotracers. The real power of PET imaging may always lie in the area of basic biomedical research, since only four CNS radiotracers (fludeoxyglucose, florbetapir, flutemetamol, and florbetaben) have been approved by the FDA for diagnostic use and companies vacillate on the value proposition of diagnostic radiotracers. When one considers basic biomedical research, the utility of a radiotracer may be harder to determine a priori but can be gauged by polling colleagues, preclinical scientists, or experts at pharmaceutical companies to determine the human translational potential of a novel radiotracer. Thus, our approach for CNS radiotracer development most often starts with unmet medical needs and uses preclinical imaging to support human translation or to set an expectation in human disease imaging.

Biological Target Selection

For any unmet clinical imaging need there may be numerous implicated biological targets and choosing among them is one of the more difficult challenges in PET radiotracer development. Unlike target selection for therapeutic development, a radiotracer target needs only to demonstrate altered expression, occupancy levels, or function in the disease state, making it a secondary, as opposed to primary, marker for the disease. As a result, there is a variety of potential biological targets for PET imaging whose measurement can be applied to broad medical and biological questions, such as differentiating among psychiatric diseases or imaging neurogenesis. (8)
Two key selection parameters for a biological target are its biochemical function and localization, which alter the strategy for identifying candidate radiotracers and influence the information obtained from the radiotracer–target interaction. Nearly all CNS radiotracers are small-molecules that interact with protein targets (Figure 2). A small subset of radiotracers are substrates for enzymes, including the preeminent CNS PET radiotracer 2-deoxy-2-[18F]fluoroglucose. In addition, radiotracers may bind to and potently inhibit the enzymes they target but without affecting the process being measured due to the small mass being administered. (11) Within the intracellular subset of targets exists the smaller group of nuclear targets, which require penetration of the nucleus by the radiotracer. These targets include enzymes involved in epigenetic modulation, such as histone deacetylases (HDACs), which have been a large focus of our lab, as well as the greater imaging community. (9, 12-15) Protein aggregates that are primarily extracellular have also been targeted for CNS PET imaging, most notably for imaging amyloid and tau deposition. (16) These biomolecules are simpler to target due to their extracellular localization; however, the designed radiotracers must penetrate the BBB.
Mirroring the development of CNS therapeutic agents, the vast majority of CNS PET radiotracers are targeted toward the intercellular domains of transmembrane proteins, including G-protein coupled receptors (GPCRs), transporters, and ion channels. (17) Radiotracers designed to bind a transmembrane protein may compete with a native ligand or be occluded by allosteric regulation. While this interaction may provide useful information on receptor occupancy, variation in the endogenous ligand concentration will confound measurement of receptor density in vivo and set requirements for the radiotracer Kd. In addition, many transmembrane receptors utilize homo- or heteropolymerization and internalization as regulatory mechanisms; (18) these altered states are difficult to recapitulate in vitro and may result in drastically different radiotracer binding affinities. New combined MR-PET approaches for relating function to ligand–receptor interactions may elucidate these mechanisms in vivo, (19) adding depth to the PET-based interrogation of the rich biology of the synapse.

Figure 2

Figure 2. Candidate biological targets for radiotracer development have diverse biochemical function and cellular localization. Established radiotracer targets include enzymes (red), receptors (blue), transporters (orange), and many other intracellular (green) and extracellular (purple) proteins.

High Resolution Image
Download MS PowerPoint Slide
An essential property that we optimize when developing binding-based radiotracers is the binding potential (BP). The BP provides a measurement of the in vivo radiotracer–target interaction and is comprised of the total biological target density (Bmax) and the binding affinity, represented as the radiotracer dissociation constant (Kd). Collective expertise in the field suggests a BP, or ratio of Bmax to Kd, of at least 5 is suitable for quantitative comparisons with PET imaging, especially in clinical research settings, but there may be scenarios where this “rule” can be violated. Radiotracers used in nonresearch clinical settings typically have a BP greater than 10. (20) When the targeted radiotracer is yet to be developed, the dissociation constant will not be known; however, we use the Bmax to estimate the ideal Kd. If the Bmax is unknown, it can be measured using autoradiography or estimated through semiquantitative immunochemical methods. (21) For radiotracers that compete with endogenous ligands in vivo, the effective target density available for radiotracer binding (Bavailable) is Bmax scaled to the fraction of targets unoccupied by the native ligand.
The percent change in expression or occupancy of the biological target is also of utmost importance and must exceed the error of the technique. The typical intrasubject test–retest variability for CNS PET radiotracers is 5–15%; (22, 23) therefore, single-subject, longitudinal changes in target density or receptor occupancy of greater than 15% can be imaged. For population comparisons, there may be high intersubject variability, which will necessarily reduce the chance of detecting these small changes. (24) For clinical evaluation of patients, even larger changes in target density or occupancy are ideal as clinicians prefer binary “yes or no” images for ease of diagnosis and treatment monitoring.
The most pragmatic factor in target selection is the existence of high-affinity small-molecule ligands with established structure–affinity relationships, typically resulting from drug development efforts. For highly novel targets without known ligands, compound library screening will be necessary. Due to the time and cost-intensive nature of de novo ligand discovery, this endeavor is best suited for targets that clearly meet the fundamental requirements for a suitable CNS PET target: high Bmax with a large percent change in density or occupancy that correlates strongly with the biomedical question to be addressed.

Radiotracer Chemical Design

Our initial ensemble of candidate radiotracers typically consists of derivatives of a known ligand of the target of interest or the hits from a high-throughput screening campaign. While radiolabeling of known ligands or even an existing therapeutic agent may seem to be the most efficient method for radiotracer development, many examples from our own lab demonstrate that this strategy often results in subpar CNS PET radiotracers due to three main factors: (1) the low mass dose used for radiotracer administration, which requires a high brain/plasma ratio for CNS imaging, (15) (2) high nonspecific binding of many therapeutic or inhibitor-adapted radiotracers in brain tissue, (14, 25-27) and (3) washout kinetics that are too slow for PET imaging. (28) Importantly, the last two factors are positive selection traits during therapeutic development because they increase and maintain target-engagement following a single administration, but these properties afford undesirable radiotracers. Efficient prioritization of candidate radiotracers based on synthetic, physiological, and biochemical constraints is required to quickly move forward to validation and preclinical imaging. (29)
For de novo synthesis of CNS radiotracers, the likelihood of discovering high-affinity, brain-penetrant molecules can be increased by concurrently synthesizing compounds with several different chemical scaffolds, as we did during HDAC radiotracer development. Additionally, scaffolds that offer several sites that can be easily substituted with various functional groups should be targeted to increase the synthetic throughput. This emphasis on high-throughput, modular syntheses is critical: in our group’s experience over 150 compounds were synthesized and over 20 were radiolabeled for non-human primate imaging during the development of a single HDAC CNS radiotracer. (15, 30) When one develops a compound library, it is also important to synthesize molecules with relatively small changes in chemical structure, since our own studies have shown that addition of a single methyl group can dramatically affect the pharmacokinetics and distribution of a molecule (Figure 3).
While an emphasis on high-throughput synthesis is essential, the chief synthetic constraint is the necessity of a facile, late-stage labeling site that can be applied to numerous derivatives. (31) By maintenance the same labeling site for many derivatives, little change in radiolabeling method is necessary between molecules, as demonstrated by the modular, peptide-based strategy for radiotracer development for predominantly peripheral targets. (32, 33) We often select 11C methylation as the labeling method to increase throughput, due to its facile and straightforward nature and its tolerability for the presence of many functional groups. (34) Application of 18F chemistry to a single, well-vetted 11C radiotracer can be achieved during the clinical transition to provide patients access to radiotracers in the absence of an in-house cyclotron. (31, 35) In some cases, high-throughput 18F fluoralkylations can be applied to a radiotracer library, (36, 37) but these fluoroalkyl groups are typically not found in CNS radiotracer scaffolds. Thus, there remain chemical limitations for 18F installation, and a continued chemical methodology effort is needed to increase the number of reliable transformations. (38-42)
Significant physiological constraints are imposed on the chemical structures of candidate CNS radiotracers. (29) To maintain radiotracer plasma levels following intravenous administration, the compounds must be bioavailable, often meeting Lipinski’s rule of five. (43) The presence of the BBB also generally limits CNS PET radiotracers to molecules that enter the brain via passive diffusion. In addition, candidate radiotracers must exhibit low nonspecific binding or binding that is nonsaturable and for which the molecular details are unclear. One common analogy for considering the impact of nonspecific binding is as follows: although the stars (specific binding) are always in the sky, we can only discern them at night because daylight (nonspecific binding) overwhelms their signal. Several physiochemical properties such as log P, log D, molecular weight, and pKa are somewhat correlated with but not necessarily predictive of the candidate radiotracer’s in vivo behavior. Computational methods to assess the physiochemical properties of potential radiotracers have been developed; (17) however, these methods do not show good agreement with a number of radiotracers our lab has developed. In the case of one chemical scaffold, the BBB penetration of the molecules was highly dependent on only two physiochemical properties, presence of a single cation and tPSA. (15) Thus, computational tools may prove useful for deciding which compound of a series to radiolabel first, but as compounds in the series are radiolabeled and tested in vivo, valuable trends often develop that can be more predictive of future success.
Another consideration for structural modification is metabolite identity, since all PET radiotracers are extensively metabolized. (29) Alterations in radiolabeled metabolite structure can result from changes in radiolabeling site, and this can impact the number of metabolites contributing to the brain signal. (29) Likewise, demethylation of 11C-methylated heteroatoms in the periphery can liberate 11C-formaldehyde, 11C-formate, or 11CO2, and defluorination can result in fluoride ion accumulation in the bone of the skull, with the resulting signal "spilling" into the brain. (44) The PET detector “sees” the radiotracer and all radiometabolites equally, so the onus is on the investigator to determine the radiochemical species producing the signal. Finally, metabolism is also species-dependent, with compounds typically metabolized more quickly in lower organisms. The differences between species extends to gross anatomy; for example, rats lack a gall bladder. Thus, there is limited validity in ruling out potential radiotracers because they failed in rodent preclinical imaging, and efforts should be made to proceed to non-human primate imaging as rapidly as possible to obtain distribution and kinetic data that is more predictive of radiotracer performance in humans.

Assessment of Radiotracer Library

With molecules in hand, the next challenge in radiotracer development is to narrow the selection of lead compounds to be radiolabeled and tested by preclinical imaging. The initial assessment of candidate radiotracers shares many similarities to the development of any small-molecule probe: affinity, selectivity, and binding kinetics are all major considerations. However, poor in vivo pharmacokinetics and high nonspecific binding are largely responsible for the high attrition rate of candidate radiotracers in the first round of preclinical imaging experiments, and these measures are not readily predictable. Therefore, we strategically assess candidate radiotracers iteratively, returning to in vitro experiments as dictated by preliminary imaging data. A comparison of data obtained from in vitro and in vivo characterization can be found in Table 1 and is discussed in detail in the following sections.
Table 1. Assessment of Key Attributes during Imaging and Nonimaging Components of Radiotracer Development
radiotracer attribute nonimaging assessment imaging assessment
binding affinity potency in in vitro assays binding potential (Bmax/Kd, smaller Kd = larger BP)
binding kinetics vary preincubation and washing steps in in vitro assays, autoradiography qualitative TAC analysis
quantitative kinetic modeling
BBB penetration mass spectrometry of unlabeled tracer %ID/cc in brain
in silico prediction
specific binding “no wash” autoradiography homologous blocking
in silico prediction knockout animals
selective binding autoradiography heterologous blocking
systematic screening (PDSP) knockout animals
In cases where we rank molecules prior to radiolabeling, we measure and compare binding affinities, which often must be subnanomolar to nanomolar, depending on the biological target density. (29, 45) The nature of this measurement will be highly dependent on the target’s biochemical function and may include displacement of a known ligand, disruption of a protein–protein interaction, formation of a covalent adduct, or inhibition of enzyme catalysis. To maximize efficiency, we optimize binding affinity assays using a known positive control concomitant with the synthesis of the radiotracer library. Once developed, the assay may be modified to measure the association or dissociation rates of the candidate molecules, which need to be relatively fast for radiotracers with short half-lives. For example, we found the kinetics of the hydroxamate class of HDAC inhibitors better suited for PET imaging than the slow-binding benzamides, despite the increased efficacy of benzamides in disease models. (21, 30) As with all in vitro biochemical assays, test–retest variation may be significant, and the protein preparation may not reflect the in vivo properties of the target. In addition, the precise ranking of the binding affinities of the potential radiotracers is less important than their general clustering.
Candidate radiotracers may also bind to off-target protein(s) that are structurally or functionally similar to the imaging target. This nonselective binding to proteins other than the target of interest is not to be confused with nonspecific binding, discussed previously. The selectivity required for a suitable radiotracer is not fixed and depends on the relative densities of the desired versus off-target proteins, as well as the relative rate of binding of the radiotracer. Furthermore, selectivity may not be problematic if the regional distribution of the off-target proteins has little anatomical overlap with the imaging target. In addition to nonselective binding based on protein homology, potential radiotracers may also have high affinities for other targets that are not easily predictable. These off-targets are best identified by systematic screening, such as the NIMH psychoactive drug screening program. (46) While off-target binding should usually be avoided, compounds that exhibit off-target binding can still show in vivo target selectivity when the target protein Bmax is high relative to off-target proteins or when the regional distribution of the target and off-target proteins is nonoverlapping. (47)
Biochemical analysis of brain tissue bridges the gap between in vitro assays and preclinical imaging. Autoradiography methods allow for facile measurement of tracer association or dissociation rates, and “no-wash” protocols are predictive of in vivo nonspecific binding. (48) However, these experiments require radiolabeling and are thus not suitable for prospective screening. If the candidate radiotracers are commercially available, it is advisable to obtain classic pharmacokinetic data prior investing in synthesis and radiolabeling. Newer mass spectrometry methods can provide information about differential distribution of unlabeled compounds throughout the brain for comparison to target protein expression levels and allow for analysis of specific and nonspecific binding across brain regions. (49) However, use of unlabeled compounds precludes measurement of the uptake and binding of compound metabolites and a large effort is required to obtain data for full pharmacokinetic analysis, because each animal can only provide information for a single time-point. This contrasts with preclinical PET imaging, wherein metabolite radioactivity can be tracked with blood analysis and full kinetic data is obtained for each injection.

Radiotracer Analysis via Preclinical Imaging

We have found that the most time-efficient assessment of new CNS radiotracers may be to bypass biochemical assessment and move directly to radiolabeling and preclinical imaging, which allows analysis and comparison of radiotracer pharmacokinetics and in vivo target engagement. Direct preclinical imaging also circumvents the disparities often found between in vitro radiotracer assessment and in vivo performance, which can cause researchers to overlook good radiotracers due to a lower binding affinity or lower selectivity between target subtypes. (33)
When analyzing preclinical imaging data, our first step is verification of radiotracer uptake in the brain. This is accomplished through plotting a time–activity curve (TAC) of the percent injected dose of radiotracer (%ID) per volume (cc) in the total brain or target-rich brain region as a function of time (Figure 3). As a guiding rule in our lab, PET radiotracers with a %ID/cc above 0.1% in rat or 0.01% in non-human primate within 5 min of injection have suitable BBB penetration for CNS PET imaging studies.

Figure 3

Figure 3. Three structurally related molecules with altered brain uptake and pharmacokinetics. (A) Chemical structure of the three molecules (1–3) that differ in the presence of methyl and phenyl groups; the ∗ indicates the 11C labeling site. (B) Transverse PET images for compounds 1–3 in baboon. (C) Time–activity curves for compounds 1–3. Adapted from ref 15.

High Resolution Image
Download MS PowerPoint Slide
If the PET radiotracer exhibits good brain uptake, the TAC can be analyzed further to determine the degree and length of radiotracer retention within in the brain. When brain retention of a radiotracer is low following a high initial brain uptake (Figure 3, compound 1), the radiotracer is potentially being actively effluxed. (50) To verify an active efflux mechanism, inhibitors of active efflux proteins, such as cyclosporin A and rifampicin, can be injected prior to the radiotracer to determine whether they increase brain retention. (50) Importantly, interspecies differences in active efflux mechanisms have been documented, (51) such that a radiotracer that fails in rodents may be suitable for non-human primate or human imaging.
When a candidate radiotracer demonstrates high brain retention, we measure the specificity of binding within the brain via homologous blocking studies, where animals are pretreated with the 12C or 19F (unlabeled) version of the radiotracer prior to radiotracer injection. If the unlabeled compound competes for binding with the radiotracer, the radiotracer signal will be reduced, indicating specific binding. Data analysis for this test requires careful attention, because blockade of binding sites by the unlabeled compound throughout the body may increase the amount of free radiotracer in plasma, resulting in increased total uptake of the radiotracer in the brain relative to untreated control animals (Figure 4a). This effect can be accounted for through normalization of radiotracer uptake to metabolite-corrected plasma radiotracer levels (Figure 4b,c), a quick assessment prior to an investment in more rigorous kinetic modeling quantification.

Figure 4

Figure 4. Impact of normalization of brain radiotracer signal to plasma radiotracer level. (A) Non-normalized baseline (blue) and self-blocked (yellow) brain signals for martinostat. (B) Integrated martinostat radioactivity in plasma during baseline (red) and self-blocked (gray) PET scans. (C) Plasma-normalized baseline (blue) and self-blocked (yellow) brain signals for martinostat. Adapted from ref 30.

High Resolution Image
Download MS PowerPoint Slide
Following verification of specific binding in the brain, we assess the presence of on-target specific binding, because some radiotracers or their metabolites may specifically bind off-target proteins. On-target specific binding analysis is typically accomplished through heterologous blocking studies in which animals are pretreated with a panel of compounds that are chemically distinct from the radiotracer and that are known to bind the biological target of interest. (10) Application of the radiotracer to knockout animal models or autoradiography (30) can be used to further verify on-target, specific binding. Autoradiography can additionally be used to correlate the regional distribution of radiotracer binding to the known regional density of the biological target. (21)
In addition to analyzing the TACs for specific binding, qualitative kinetic analysis can be performed to determine whether the radiotracer is suitable for human imaging. While kinetic properties vary between species, kinetics suitable for robust quantitative analysis can typically be spotted through comparison of TAC slopes at time points after the peak signal. A relatively steeper curve (faster radiotracer washout) following treatment with the nonradioactive radiotracer analog indicates a measurable decrease in BP, even without accounting for changes in plasma radiotracer activity (Figure 4a). A slope near zero may be indicative of a radiotracer with irreversible binding or too-slow kinetics. To interrogate these radiotracers, we complete a bolus or bolus-plus-infusion experiment with injection of a homologous or heterologous blocking agent midscan. A decrease in slope after blocking agent administration indicates a BP decrease, and therefore measurable, reversible binding. The quantitative kinetic analysis of radiotracer binding is the topic of several comprehensive reviews. (45, 52, 53)
When moving to preclinical imaging, we have found many instances in which a new radiolabeled compound either did not penetrate the BBB or did not show specific, on-target binding, which required a return to radiotracer design. At times, validation of a new biological target is necessary, for example, when several molecular scaffolds for the initial target have failed to show brain uptake or specific binding. However, with persistence and preclinical assessment of many radiotracers, CNS PET radiotracers with high brain uptake, specific on-target binding, and a suitable kinetic profile can be discovered.

Conclusion and Guiding Principles

ARTICLE SECTIONS
Jump To
Novel radiotracer development is a challenging endeavor, requiring knowledge of disease-related biological targets, chemical synthesis and radiolabeling, in vitro assay development, and image analysis. Biomedical questions should be applicable to human clinical studies and more feasible to answer with PET imaging versus other, possibly less resource-intensive, tools. When the need for a novel radiotracer is established, we make use of the following principles to guide our development program:

1 Know Your Biology

In-house analysis of tissue slices, cell cultures, and protein preparations is paramount to determine the density and regional brain distribution of the target, the change in target density or occupancy, and the binding affinities of lead candidate radiotracers. By doing these assays in the environment of radiotracer discovery, you will gain insight into peculiarities of the biological target and candidate radiotracers that may be valuable during in vivo assessment.

2 Throughput Matters

The structural design of candidate radiotracers must be amenable to late-stage diversification and facile radiolabeling, because many iterations of a chemical series may be needed before a suitable tracer is identified. Biochemical assays of binding affinity can be developed into a high-throughput screen.

3 Aim for Studies in Humans

Low brain penetration, high nonspecific binding, and a poor metabolic profile are the primary factors that eliminate candidate radiotracers in the preclinical imaging stage, but these measures are highly species-dependent. When possible, radiotracers should be assessed in non-human primates, with the goal of moving to human imaging as soon as possible.
Finally, one should remain optimistic. As depicted in Figure 1, the process of PET radiotracer development is often iterative and circuitous, requiring the designer to frequently step back and assess the current best path forward. After the initial biomedical question is posed, the succeeding components (pools) of target selection, chemical design, library assessment, and preclinical imaging may be revisited many times and in variant orders (streams) before a suitable radiotracer (central water burst) is developed that is poised to provide an answer.

Author Information

ARTICLE SECTIONS
Jump To
  • Corresponding Author
    • Jacob M. Hooker - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States;  Email: [email protected]
  • Authors
    • Genevieve C. Van de Bittner - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States
    • Emily L. Ricq - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States;  Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
  • Notes
    The authors declare no competing financial interest.

Biographies

ARTICLE SECTIONS
Jump To

Genevieve C. Van de Bittner

Download MS PowerPoint Slide

Genevieve Van de Bittner obtained a Ph.D. in Chemistry from the University of California, Berkeley, in 2012. She is currently completing a postdoctoral fellowship at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital, in affiliation with Harvard Medical School. Her current research focus is the development of radiotracers for synapse imaging in humans.

Emily L. Ricq

Download MS PowerPoint Slide

Emily Ricq received her B.Sc. in Chemistry from the University of Arizona in 2010 and is pursuing her Ph.D. in Chemistry & Chemical Biology from Harvard University. Her current research focuses on developing chemical tools to profile epigenetic processes relevant to neurobiology.

Jacob M. Hooker

Download MS PowerPoint Slide

Jacob Hooker received his Ph.D. at UC Berkeley in 2007 in Chemistry. After a postdoctoral fellowship at Brookhaven National Laboratory, Prof. Hooker moved to the Martinos Center for Biomedical Imaging at Massachusetts General Hospital in 2009. He is currently an Assistant Professor at Harvard Medical School where he and his team work on new human neuroimaging technologies and their applications to brain disorders.

Acknowledgment

ARTICLE SECTIONS
Jump To

We acknowledge Aaron Keefe for creating the artwork in Figure 1, which illustrates the authors’ fountain-based view of the radiotracer development process. We thank the members of the Hooker Lab for their insight and advice and Dr. Changning Wang for contribution of data. We acknowledge the National Institutes of Health (Grant NIH R01:5R01DA030321) and the Department of Energy (DOE Training Grant DE-SC0008430) for funding this work.

Abbreviations

ARTICLE SECTIONS
Jump To
PET

positron emission tomography
CNS

central nervous system
BBB

blood–brain barrier
GPCRs

G-protein coupled receptors
MR-PET

magnetic resonance-positron emission tomography
BP

binding potential
TAC

time–activity curve

References

ARTICLE SECTIONS
Jump To

This article references 53 other publications.

  1. 1
    Lockwood, A. H. Invasiveness in Studies of Brain Function by Positron Emission Tomography (PET) J. Cereb. Blood Flow Metab. 1985, 5, 487– 489
    Google Scholar
    1
    Invasiveness in studies of brain function by positron emission tomography (PET)
    Lockwood A H
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (1985), 5 (4), 487-9 ISSN:0271-678X.
    There is no expanded citation for this reference.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL28%252FjsVaitA%253D%253D&md5=0e851326d4c65e86b2d46adf77a46470
  2. 2
    Eriksson, L.; Kanno, I. Blood Sampling Devices and Measurements Med. Prog. Technol. 1991, 17, 249– 257
    Google Scholar
    2
    Blood sampling devices and measurements
    Eriksson L; Kanno I
    Medical progress through technology (1991), 17 (3-4), 249-57 ISSN:0047-6552.
    Quantitative positron emission tomography requires the determination of the tracer concentration in arterial plasma or full blood as a function of time. This defines the experimental input function. The model prediction, with which the positron camera regional time-activity curves are compared, is given by the experimental input function convoluted with the model. This paper reviews different strategies for determining the input function, invasive techniques, such as manual blood sampling and the use of automated blood sampling systems, and non-invasive techniques. The importance of corrections is discussed, such as accurate cross-calibrations of the different detectors used in quantitative PET and corrections for differences in time phase between the regional PET time-activity curves and the input function. We also report on the use of a PET system in non-invasive determinations of the input function. By imaging the neck region the time-activity curve of the carotid arteries can be obtained. The PET time-activity curves of the carotid arteries are in good agreement with a conventional experimental input function determined from the radial artery with an automated blood sampling system. However, PET time-activity curves of the radial arteries can not be used without a deconvolution since the resistance in the intact radial artery causes dispersion compared to the input function obtained by invasive methods.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK383lt1OlsQ%253D%253D&md5=38fa8d292c658c13a29dafcfcf245d33
  3. 3
    Zimmer, L.; Luxen, A. PET Radiotracers for Molecular Imaging in the Brain: Past, Present and Future NeuroImage 2012, 61, 363– 370
    Google Scholar
    There is no corresponding record for this reference.
  4. 4
    Hargreaves, R. J.; Rabiner, E. A. Translational PET Imaging Research Neurobiol. Dis. 2014, 61, 32– 38
    Google Scholar
    4
    Translational PET imaging research
    Hargreaves Richard J; Rabiner Eugenii A
    Neurobiology of disease (2014), 61 (), 32-8 ISSN:.
    The goal of any early central nervous system (CNS) drug development program is always to test the mechanism and not the molecule in order to support additional research investments in late phase clinical trials. Confirmation that drugs reach their targets using translational positron emission tomography (PET) imaging markers of engagement is central to successful clinical proof-of-concept testing and has become an important feature of most neuropsychiatric drug development programs. CNS PET imaging can also play an important role in the clinical investigation of the neuropharmacological basis of psychiatric disease and the optimization of drug therapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252FgtVGlsg%253D%253D&md5=84b76b18c4006d60f1b420ae0ebeb903
  5. 5
    CNS Radiotracer Table http://www.nimh.nih.gov/research-priorities/therapeutics/cns-radiotracer-table.shtml (accessed Jun 17, 2014) .
    Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Martins-de-Souza, D.; Carvalho, P. C.; Schmitt, A.; Junqueira, M.; Nogueira, F. C. S.; Turck, C. W.; Domont, G. B. Deciphering the Human Brain Proteome: Characterization of the Anterior Temporal Lobe and Corpus Callosum as Part of the Chromosome 15-Centric Human Proteome Project J. Proteome Res. 2014, 13, 147– 157
    Google Scholar
    6
    Deciphering the Human Brain Proteome: Characterization of the Anterior Temporal Lobe and Corpus Callosum As Part of the Chromosome 15-centric Human Proteome Project
    Martins-de-Souza, Daniel; Carvalho, Paulo C.; Schmitt, Andrea; Junqueira, Magno; Nogueira, Fabio C. S.; Turck, Christoph W.; Domont, Gilberto B.
    Journal of Proteome Research (2014), 13 (1), 147-157CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    Defining the proteomes encoded by each chromosome and characterizing proteins related to human illnesses are among the goals of the Chromosome-centric Human Proteome Project (C-HPP) and the Biol. and Disease-driven HPP. Following these objectives, the authors studied the proteomes of the human anterior temporal lobe (ATL) and corpus callosum (CC) collected post-mortem from eight subjects. Using a label-free GeLC-MS/MS approach, the authors identified 2454 proteins in the ATL and 1887 in the CC through roughly 7500 and 5500 peptides, resp. Considering that the ATL is a gray-matter region while the CC is a white-matter region, they presented proteomes specific to their functions. Besides, 38 proteins are differentially expressed between the two regions. Furthermore, the proteome data sets were classified according to their chromosomal origin, and five proteins were evidenced at the MS level for the first time. The authors identified 70 proteins of the chromosome 15 - one of them for the first time by MS - which were submitted to an in silico pathway anal. These revealed branch point proteins assocd. with Prader-Willi and Angelman syndromes and dyskeratosis congenita, which are chromosome-15-assocd. diseases. Data presented here can be a useful for brain disorder studies as well as for contributing to the C-HPP initiative. The authors' data are publicly available as resource data to C-HPP participant groups at http://yoda.iq.ufrj.br/Daniel/chpp2013. Addnl., the mass spectrometry proteomics data have been deposited to the ProteomeXchange with identifier PXD000547 for the corpus callosum and PXD000548 for the anterior temporal lobe.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVCisL%252FE&md5=af81b7085d9ae5bb39e55342517a00f8
  7. 7
    Jones, T.; Rabiner, E. A. PET Research Advisory Company. The Development, Past Achievements, and Future Directions of Brain PET J. Cereb. Blood Flow Metab. 2012, 32, 1426– 1454
    Google Scholar
    7
    The development, past achievements, and future directions of brain PET
    Jones, Terry; Rabiner, Eugenii A.
    Journal of Cerebral Blood Flow & Metabolism (2012), 32 (7), 1426-1454CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)
    A review. The early developments of brain positron emission tomog. (PET), including the methodol. advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clin. applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodol. and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochem. technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments. Journal of Cerebral Blood Flow & Metab. (2012) 32, 1426-1454; doi:10.1038/jcbfm.2012.20; published online 21 March 2012.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVSjtr8%253D&md5=4175eb96622d701f626088265b81265a
  8. 8
    Ho, N. F.; Hooker, J. M.; Sahay, A.; Holt, D. J.; Roffman, J. L. In Vivo Imaging of Adult Human Hippocampal Neurogenesis: Progress, Pitfalls and Promise Mol. Psychiatry 2013, 18, 404– 416
    Google Scholar
    8
    In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise
    Ho N F; Hooker J M; Sahay A; Holt D J; Roffman J L
    Molecular psychiatry (2013), 18 (4), 404-16 ISSN:.
    New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult-born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot establish its functional importance in human health, disease and new treatment development. Current non-invasive neuroimaging modalities can provide live snapshots of the brain's structure, chemistry, activity and connectivity. This review explores whether existing macroscopic imaging methods can be used to understand the microscopic dynamics of adult hippocampal neurogenesis in living individuals. We discuss recent studies that have found correlations between neuroimaging measures of human hippocampal biology and levels of pro- or anti-neurogenic stimuli, weigh whether these correlations reflect changes in adult neurogenesis, detail the conceptual and technical limitations of these studies and elaborate on what will be needed to validate in vivo neuroimaging measures of adult neurogenesis for future investigations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svhtFGrtw%253D%253D&md5=6f5fe4614c5f101b2ff65054cf7edae8
  9. 9
    Wang, C.; Schroeder, F. A.; Hooker, J. M. Visualizing Epigenetics: Current Advances and Advantages in HDAC PET Imaging Techniques Neuroscience 2014, 264, 186– 197
    Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Schroeder, F. A.; Wang, C.; Van de Bittner, G.; Neelamegam, R.; Takakura, W.; Karunakaran, P.; Wey, H.-Y.; Reis, S.; Gale, J. P.; Zhang, Y.-L.; Holson, E.; Haggarty, S.; Hooker, J. PET Imaging Demonstrates Histone Deacetylase Target Engagement and Clarifies Brain Penetrance of Known and Novel Small Molecule Inhibitors in Rat ACS Chem. Neurosci. 2014,  DOI: 10.1021/cn500162j
    Google Scholar
    There is no corresponding record for this reference.
  11. 11
    Biegon, A.; Kim, S. W.; Alexoff, D. L.; Jayne, M.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J. S. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies with PET and [N-Methyl-11C]vorozole Synapse 2010, 64, 801– 807
    Google Scholar
    There is no corresponding record for this reference.
  12. 12
    Kim, S. W.; Hooker, J. M.; Otto, N.; Win, K.; Muench, L.; Shea, C.; Carter, P.; King, P.; Reid, A. E.; Volkow, N. D.; Fowler, J. S. Whole-Body Pharmacokinetics of HDAC Inhibitor Drugs, Butyric Acid, Valproic Acid and 4-Phenylbutyric Acid Measured with Carbon-11 Labeled Analogs by PET Nucl. Med. Biol. 2013, 40, 912– 918
    Google Scholar
    12
    Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET
    Kim, Sung Won; Hooker, Jacob M.; Otto, Nicola; Win, Khaing; Muench, Lisa; Shea, Colleen; Carter, Pauline; King, Payton; Reid, Alicia E.; Volkow, Nora D.; Fowler, Joanna S.
    Nuclear Medicine and Biology (2013), 40 (7), 912-918CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
    The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to det. the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogs and performed dynamic positron emission tomog. (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepd. by using 11CO2 and the appropriate Grignard reagents. [11C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compd. at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compd. at 30 min after their administration resp. The brain uptake of all three carboxylic acids was very low (< 0.006%ID/cc, BA > VPA > PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [11C]BA showed relatively high uptake in spleen and pancreas whereas [11C]PBA showed high uptake in liver and heart. Notably, [11C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metab. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFynt77P&md5=fdc05c5c4822dfff4ffa9e7eee8f80dc
  13. 13
    Seo, Y. J.; Muench, L.; Reid, A.; Chen, J.; Kang, Y.; Hooker, J. M.; Volkow, N. D.; Fowler, J. S.; Kim, S. W. Radionuclide Labeling and Evaluation of Candidate Radioligands for PET Imaging of Histone Deacetylase in the Brain Bioorg. Med. Chem. Lett. 2013, 23, 6700– 6705
    Google Scholar
    There is no corresponding record for this reference.
  14. 14
    Wang, C.; Eessalu, T. E.; Barth, V. N.; Mitch, C. H.; Wagner, F. F.; Hong, Y.; Neelamegam, R.; Schroeder, F. A.; Holson, E. B.; Haggarty, S. J.; Hooker, J. M. Design, Synthesis, and Evaluation of Hydroxamic Acid-Based Molecular Probes for in Vivo Imaging of Histone Deacetylase (HDAC) in Brain Am. J. Nucl. Med. Mol. Imaging 2013, 4, 29– 38
    Google Scholar
    14
    Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain
    Wang Changning; Neelamegam Ramesh; Hooker Jacob M; Eessalu Thomas E; Barth Vanessa N; Mitch Charles H; Wagner Florence F; Holson Edward B; Hong Yijia; Schroeder Frederick A; Haggarty Stephen J
    American journal of nuclear medicine and molecular imaging (2013), 4 (1), 29-38 ISSN:2160-8407.
    Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czhtFersw%253D%253D&md5=2838a5695f30ae031ca6f97d26dc7250
  15. 15
    Seo, Y. J.; Kang, Y.; Muench, L.; Reid, A.; Caesar, S.; Jean, L.; Wagner, F.; Holson, E.; Haggarty, S. J.; Weiss, P.; King, P.; Carter, P.; Volkow, N. D.; Fowler, J. S.; Hooker, J. M.; Kim, S. W. Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors ACS Chem. Neurosci. 2014, 5, 588– 596
    Google Scholar
    15
    Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors
    Seo, Young Jun; Kang, Yeona; Muench, Lisa; Reid, Alicia; Caesar, Shannon; Jean, Logan; Wagner, Florence; Holson, Edward; Haggarty, Stephen J.; Weiss, Philipp; King, Payton; Carter, Pauline; Volkow, Nora D.; Fowler, Joanna S.; Hooker, Jacob M.; Kim, Sung Won
    ACS Chemical Neuroscience (2014), 5 (7), 588-596CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addn. to low HDAC potency and selectivity obsd., poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here the authors report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compds. based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compd. to feed back into the design process. A total of 17 compds. were evaluated, revealing mols. with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivs. exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivs. showed high BBB penetration (∼0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate mols. for small mol. probes and drugs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmvF2msb4%253D&md5=c59102403f07049034e1cd0a47161eb6
  16. 16
    Nordberg, A. PET Tracers for Beta-Amyloid and Other Proteinopathies. In PET and SPECT of Neurobiological Systems; Dierckx, R. A. J. O.; Otte, A.; de Vries, E. F. J.; van Waarde, A.; Luiten, P. G. M., Eds.; Springer: Berlin Heidelberg, 2014; pp 199– 212.
    Google Scholar
    There is no corresponding record for this reference.
  17. 17
    Zhang, L.; Villalobos, A.; Beck, E. M.; Bocan, T.; Chappie, T. A.; Chen, L.; Grimwood, S.; Heck, S. D.; Helal, C. J.; Hou, X.; Humphrey, J. M.; Lu, J.; Skaddan, M. B.; McCarthy, T. J.; Verhoest, P. R.; Wager, T. T.; Zasadny, K. Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand J. Med. Chem. 2013, 56, 4568– 4579
    Google Scholar
    17
    Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand
    Zhang, Lei; Villalobos, Anabella; Beck, Elizabeth M.; Bocan, Thomas; Chappie, Thomas A.; Chen, Laigao; Grimwood, Sarah; Heck, Steven D.; Helal, Christopher J.; Hou, Xinjun; Humphrey, John M.; Lu, Jiemin; Skaddan, Marc B.; McCarthy, Timothy J.; Verhoest, Patrick R.; Wager, Travis T.; Zasadny, Kenneth
    Journal of Medicinal Chemistry (2013), 56 (11), 4568-4579CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    To accelerate the discovery of novel small mol. central nervous system (CNS) positron emission tomog. (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET ligands that have successfully reached the clinic and 15 radioligands that failed in late-stage development as neg. controls. A systematic anal. of these ligands identified a set of preferred parameters for physicochem. properties, brain permeability, and nonspecific binding (NSB). These preferred parameters have subsequently been applied to several programs and have led to the successful development of novel PET ligands with reduced resources and timelines. This strategy is illustrated here by the discovery of the novel phosphodiesterase 2A (PDE2A) PET ligand 4-(3-[18F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine, [18F]PF-05270430 (5).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntFyhtro%253D&md5=ee7ce04829d7456a632c02c331c4edfa
  18. 18
    Ferré, S.; Casadó, V.; Devi, L. A.; Filizola, M.; Jockers, R.; Lohse, M. J.; Milligan, G.; Pin, J.-P.; Guitart, X. G Protein-Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives Pharmacol. Rev. 2014, 66, 413– 434
    Google Scholar
    There is no corresponding record for this reference.
  19. 19
    Sander, C. Y.; Hooker, J. M.; Catana, C.; Normandin, M. D.; Alpert, N. M.; Knudsen, G. M.; Vanduffel, W.; Rosen, B. R.; Mandeville, J. B. Neurovascular Coupling to D2/D3 Dopamine Receptor Occupancy Using Simultaneous PET/functional MRI Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 11169– 11174
    Google Scholar
    There is no corresponding record for this reference.
  20. 20
    Patel, S.; Gibson, R. In Vivo Site-Directed Radiotracers: A Mini-Review Nucl. Med. Biol. 2008, 35, 805– 815
    Google Scholar
    20
    In vivo site-directed radiotracers: a mini-review
    Patel, Shil; Gibson, Raymond
    Nuclear Medicine and Biology (2008), 35 (8), 805-815CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)
    A review on the process for developing reversible, monovalent site-specific radiotracers in drug design. It is concerned with the characteristics of radiotracers such as binding, lipophilicity, and binding specificity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVaisLvL&md5=869985e0741d52a76cb546972097e2a8
  21. 21
    Wang, Y.; Zhang, Y.-L.; Hennig, K.; Gale, J. P.; Hong, Y.; Cha, A.; Riley, M.; Wagner, F.; Haggarty, S. J.; Holson, E.; Hooker, J. Class I HDAC Imaging Using [(3)H]CI-994 Autoradiography Epigenetics 2013, 8, 756– 764
    Google Scholar
    There is no corresponding record for this reference.
  22. 22
    Gage, H. D.; Voytko, M. L.; Ehrenkaufer, R. L.; Tobin, J. R.; Efange, S. M.; Mach, R. H. Reproducibility of Repeated Measures of Cholinergic Terminal Density Using [18F](+)-4-Fluorobenzyltrozamicol and PET in the Rhesus Monkey Brain J. Nucl. Med. 2000, 41, 2069– 2076
    Google Scholar
    There is no corresponding record for this reference.
  23. 23
    Narendran, R.; Mason, N. S.; May, M. A.; Chen, C.-M.; Kendro, S.; Ridler, K.; Rabiner, E. A.; Laruelle, M.; Mathis, C. A.; Frankle, W. G. Positron Emission Tomography Imaging of Dopamine D2/3 Receptors in the Human Cortex with [11C]FLB 457: Reproducibility Studies Synapse 2011, 65, 35– 40
    Google Scholar
    There is no corresponding record for this reference.
  24. 24
    Wahl, L. M.; Nahmias, C. Statistical Power Analysis for PET Studies in Humans J. Nucl. Med. 1998, 39, 1826– 1829
    Google Scholar
    There is no corresponding record for this reference.
  25. 25
    Stephenson, K. A.; van Oosten, E. M.; Wilson, A. A.; Meyer, J. H.; Houle, S.; Vasdev, N. Synthesis and Preliminary Evaluation of [(18)F]-Fluoro-(2S)-Exaprolol for Imaging Cerebral Beta-Adrenergic Receptors with PET Neurochem. Int. 2008, 53, 173– 179
    Google Scholar
    25
    Synthesis and preliminary evaluation of [18F]-fluoro-(2S)-Exaprolol for imaging cerebral β-adrenergic receptors with PET
    Stephenson, Karin A.; van Oosten, Erik M.; Wilson, Alan A.; Meyer, Jeffrey H.; Houle, Sylvain; Vasdev, Neil
    Neurochemistry International (2008), 53 (5), 173-179CODEN: NEUIDS; ISSN:0197-0186. (Elsevier B.V.)
    Cerebral β-adrenergic receptors (β-ARs) are of interest in several disorders including Parkinson's disease, Alzheimer's disease and in particular major depressive disorder. Development of a positron emission tomog. (PET) ligand for imaging β-ARs would allow the quantification of these receptors in the living human brain so as to better understand both the pathophysiol. of depression and how to improve treatment. Currently there are no radioligands suitable for this purpose. In an attempt to achieve this goal, we prepd. [18F]-labeled (2S)-1-(1-fluoropropan-2-ylamino)-3-(2-cyclohexylphenoxy)propan-2-ol (fluoro-Exaprolol; (2 S )-1). Radiolabeling with fluorine-18 was accomplished via prepn. of a precursor contg. a tosyl leaving group (10), and utilizes the 2-oxazolidinone group to simultaneously protect both the amine and hydroxy groups. The oxazolidinone was readily removed with lithium aluminum hydride following a nucleophilic [18F]-fluoride for tosyl displacement to prep. [18 F]-(2 S)-1 in 31% radiochem. yield (uncorrected for decay), with >98% radiochem. purity in <1 h. The specific activity of the formulated product was 927 mCi/μmol and the log P (pH 7.4) was 2.97. Preliminary biol. evaluations in conscious rats indicated that [18 F]-(2 S)-1 had good brain uptake for imaging (0.8-1.3% injected dose/g (% ID/g) of wet tissue, 5 min post-injection of the radiotracer) with a slow washout (>0.5% ID/g at 60 min post-injection) in all brain regions. Pharmacol. challenges indicate that the binding is largely non-specific, as administration of Propranolol, authentic (2 S)-1, or WAY 100635 prior to injection of [18 F]-(2 S)-1 did not block uptake of the radiotracer. These results indicate that [18 F]-(2 S)-1 is not a suitable candidate for PET imaging of cerebral β-ARs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFOltbjJ&md5=0832cfa393ee025f12dc4624737670c8
  26. 26
    Wang, C.; Wilson, C. M.; Moseley, C. K.; Carlin, S. M.; Hsu, S.; Arabasz, G.; Schroeder, F. A.; Sander, C. Y.; Hooker, J. M. Evaluation of Potential PET Imaging Probes for the Orexin 2 Receptors Nucl. Med. Biol. 2013, 40, 1000– 1005
    Google Scholar
    26
    Evaluation of potential PET imaging probes for the orexin 2 receptors
    Wang, Changning; Wilson, Colin M.; Moseley, Christian K.; Carlin, Stephen M.; Hsu, Shirley; Arabasz, Grae; Schroeder, Frederick A.; Sander, Christin Y.; Hooker, Jacob M.
    Nuclear Medicine and Biology (2013), 40 (8), 1000-1005CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
    A wide range of central nervous system (CNS) disorders, particularly those related to sleep, are assocd. with the abnormal function of orexin (OX) receptors. Several orexin receptor antagonists have been reported in recent years, but currently there are no imaging tools to probe the d. and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomog. (PET) radiotracer development could be used to elucidate the assocn. of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compds. based on diazepane orexin receptor antagonists previously described. One of the synthesized compds., [11C]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR imaging. PET scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [11C]CW4 exhibited fast kinetics and high nonspecific binding, as detd. after co-administration of [11C]CW4 and unlabeled CW4. These properties indicate that [11C]CW4 has excellent brain penetrance and could be used as a lead compd. for developing new CNS-penetrant PET imaging probes of orexin receptors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yhsrvK&md5=3219170035ebadd30300dd139ceb3883
  27. 27
    Neelamegam, R.; Hellenbrand, T.; Schroeder, F. A.; Wang, C.; Hooker, J. M. Imaging Evaluation of 5HT2C Agonists, [(11)C]WAY-163909 and [(11)C]Vabicaserin, Formed by Pictet-Spengler Cyclization J. Med. Chem. 2014, 57, 1488– 1494
    Google Scholar
    There is no corresponding record for this reference.
  28. 28
    Horti, A. G.; Gao, Y.; Kuwabara, H.; Dannals, R. F. Development of Radioligands with Optimized Imaging Properties for Quantification of Nicotinic Acetylcholine Receptors by Positron Emission Tomography Life Sci. 2010, 86, 575– 584
    Google Scholar
    There is no corresponding record for this reference.
  29. 29
    Pike, V. W. PET Radiotracers: Crossing the Blood-Brain Barrier and Surviving Metabolism Trends Pharmacol. Sci. 2009, 30, 431– 440
    Google Scholar
    29
    PET radiotracers: crossing the blood-brain barrier and surviving metabolism
    Pike, Victor W.
    Trends in Pharmacological Sciences (2009), 30 (8), 431-440CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)
    A review. Radiotracers for imaging protein targets in the living human brain with positron emission tomog. (PET) are increasingly useful in clin. research and in drug development. Such radiotracers must fulfill many criteria, among which an ability to enter brain adequately and reversibly without contamination by troublesome radiometabolites is desirable for accurate measurement of the d. of a target protein (e.g. neuroreceptor, transporter, enzyme or plaque). Candidate radiotracers can fail as a result of poor passive brain entry, rejection from brain by efflux transporters or undesirable metab. These issues are reviewed. Emerging PET radiotracers for measuring efflux transporter function and new strategies for ameliorating radiotracer metab. are discussed. A growing understanding of the mol. features affecting the brain penetration, metab. and efflux transporter sensitivity of prospective radiotracers should ultimately lead to their more rational and efficient design, and also to their greater efficacy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpt1KgsLg%253D&md5=97704995fecd968baf1e0892bf70324e
  30. 30
    Wang, C.; Schroeder, F. A.; Wey, H.-Y.; Borra, R.; Wagner, F.; Reis, S.; Kim, S. W.; Holson, E. B.; Haggarty, S. J.; Hooker, J. M. In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs J. Med. Chem. 2014,  DOI: 10.1021/jm500872p
    Google Scholar
    There is no corresponding record for this reference.
  31. 31
    Hooker, J. M. Modular Strategies for PET Imaging Agents Curr. Opin. Chem. Biol. 2010, 14, 105– 111
    Google Scholar
    31
    Modular strategies for PET imaging agents
    Hooker, Jacob M.
    Current Opinion in Chemical Biology (2010), 14 (1), 105-111CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    A review. In recent years, modular and simplified chem. and biol. strategies have been developed for the synthesis and implementation of positron emission tomog. (PET) radiotracers. New developments in bioconjugation and synthetic methodologies, in combination with advances in macromol. delivery systems and gene-expression imaging, reflect a need to reduce radiosynthesis burden in order to accelerate imaging agent development. These new approaches, which are often mindful of existing infrastructure and available resources, are anticipated to provide a more approachable entry point for researchers interested in using PET to translate in vitro research to in vivo imaging.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht12qt7w%253D&md5=2933036c778dcd76b3cdf2afc4067909
  32. 32
    Sutcliffe-Goulden, J. L.; O’Doherty, M. J.; Marsden, P. K.; Hart, I. R.; Marshall, J. F.; Bansal, S. S. Rapid Solid Phase Synthesis and Biodistribution of 18F-Labelled Linear Peptides Eur. J. Nucl. Med. Mol. Imaging 2002, 29, 754– 759
    Google Scholar
    32
    Rapid solid phase synthesis and biodistribution of 18F-labeled linear peptides
    Sutcliffe-Goulden, Julie L.; O'Doherty, Michael J.; Marsden, Paul K.; Hart, Ian R.; Marshall, John F.; Bansal, Sukvinder S.
    European Journal of Nuclear Medicine and Molecular Imaging (2002), 29 (6), 754-759CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)
    A rapid method for radiolabeling short peptides with 18F (t1/2=109.7 min) for use in positron emission tomog. (PET) was developed. Linear peptides (13-mers) were synthesized using solid phase peptide synthesis and 9-fluorenylmethoxycarbonyl (Fmoc) chem. The peptides were assembled on a solid-phase polyethylene glycol-polystyrene support using the "hyper acid labile" linker xanthen-2-oxyvaleric acid and were labeled in situ with 4-[19F]- or 4-[18F]fluorobenzoic acid. Optimum coupling of 4-[19F]fluorobenzoic acid to the peptidyl resin was achieved within 2 min using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU/DIPEA), and optimum cleavage was achieved within 7 min using trifluoroacetic acid/phenol/water/Triisopropylsilane at 37°C. The linear peptides were rapidly labeled with 4-[18F]fluorobenzoic acid with an overall radiochem. yield of 80%-90% (decay cor.), a radiochem. purity of >95% without HPLC purifn. and an overall synthesis time of 20 min. This novel method was used to label peptides contg. the arginine-glycine-aspartic acid (RGD) motif, the binding site of many integrins. In vitro studies showed that the fluorobenzoyl prosthetic group had no deleterious effect on the ability of these peptides to inhibit the binding of human cells via integrins. Biodistribution studies in tumor-bearing mice showed that although the linear peptides were rapidly removed from the circulation by the liver and kidneys, there was a transient and non-RGD-dependent accumulation in the tumor of both the test and the control peptides. The use of more selective peptides with a longer half-life in the circulation combined with this rapid labeling technique will significantly enhance the application of peptides in PET.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvVWnu7s%253D&md5=b7cf5a3b76bb3fdcf48e8a0fd2ad18e6
  33. 33
    Gagnon, M. K. J.; Hausner, S. H.; Marik, J.; Abbey, C. K.; Marshall, J. F.; Sutcliffe, J. L. High-Throughput in Vivo Screening of Targeted Molecular Imaging Agents Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 17904– 17909
    Google Scholar
    There is no corresponding record for this reference.
  34. 34
    Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Synthesis of 11C, 18F, 15O, and 13N Radiolabels for Positron Emission Tomography Angew. Chem., Int. Ed. 2008, 47, 8998– 9033
    Google Scholar
    There is no corresponding record for this reference.
  35. 35
    Cole, E. L.; Stewart, M. N.; Littich, R.; Hoareau, R.; Scott, P. J. H. Radiosyntheses Using Fluorine-18: The Art and Science of Late Stage Fluorination Curr. Top. Med. Chem. 2014, 14, 875– 900
    Google Scholar
    35
    Radiosyntheses using Fluorine-18: The Art and Science of Late Stage Fluorination
    Cole, Erin L.; Stewart, Megan N.; Littich, Ryan; Hoareau, Raphael; Scott, Peter J. H.
    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (7), 875-900CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
    A review. Positron (β+) emission tomog. (PET) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiol. structures and biochem. pathways. The continued growth of PET imaging relies on a corresponding increase in access to radiopharmaceuticals (biol. active mols. labeled with short-lived radionuclides such as fluorine-18). This unique need to incorporate the short-lived fluorine-18 atom (t1/2 = 109.77 min) as late in the synthetic pathway as possible has made development of methodologies that enable rapid and efficient late stage fluorination an area of research within its own right. In this review we describe strategies for radiolabeling with fluorine-18, including classical fluorine-18 radiochem. and emerging techniques for late stage fluorination reactions, as well as labeling technologies such as microfluidics and solid-phase radiochem. The utility of fluorine-18 labeled radiopharmaceuticals is showcased through recent applications of PET imaging in the healthcare, personalized medicine and drug discovery settings.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlt1SgtbY%253D&md5=25ced9ea824e1c9e6dd55bc91bda4fdd
  36. 36
    Zhang, M.-R.; Suzuki, K. [18F]Fluoroalkyl Agents: Synthesis, Reactivity and Application for Development of PET Ligands in Molecular Imaging Curr. Top. Med. Chem. 2007, 7, 1817– 1828
    Google Scholar
    36
    [18F]fluoroalkyl agents: synthesis, reactivity and application for development of PET ligands in molecular imaging
    Zhang, Ming-Rong; Suzuki, Kazutoshi
    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2007), 7 (18), 1817-1828CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
    A review. Fluorine-18 (18F, β+; 96.7%, T1/2 = 109.8 min) is of considerable importance for developing positron emission tomog. (PET) ligands for imaging receptor, enzyme, gene expression etc. in brain, tumor, myocardium and other regions or organs due to its optimal decay characteristics. To synthesize 18F-labeled PET ligands, reliable labeling techniques inserting 18F into a target mol. are necessary. [18F]Fluoroalkylation is a useful way of introducing 18F into target mols. contg. amino, phenol, thiophenol, and amide functional groups. Here, the authors review the prepn., reactivity and application of [18F]fluoroalkyl agents for the development of 18F-labeled PET ligands in mol. imaging. [18F]Fluoroalkyl agents have been synthesized by reacting [18F]F- with the corresponding alkyl derivs. contg. halogen and sulfonate as leaving groups. After the fluorination reaction, the radiolabeled products with relatively low b.ps. were distd. from the reaction mixts., sometimes added by Sep-Pak or gas chromatog. sepn. The [18F]fluoromethyl compds. have high reactivity with nucleophilic substrates, but many [18F]fluoromethylated compds. are in vitro unstable. To increase the efficiency of [18F]fluoroethylation, [18F]FCH2CH2Br, the most frequently used [18F]fluoroethyl agent, was converted into [18F]FCH2CH2I or [18F]FCH2CH2OTf in situ. Most [18F]fluoromethylated ligands were found to be in vivo unstable due to defluorination. Deuterium substitution for the fluoromethyl group reduced defluorination to an extent. A no. of [18F]fluoroethylated PET ligands have been developed for animal evaluation and clin. investigation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVOrtb3F&md5=9a962abf194338e920477c5ca32703f0
  37. 37
    Pretze, M.; Pietzsch, D.; Mamat, C. Recent Trends in Bioorthogonal Click-Radiolabeling Reactions Using Fluorine-18 Molecules 2013, 18, 8618– 8665
    Google Scholar
    37
    Recent trends in bioorthogonal click-radiolabeling reactions using fluorine-18
    Pretze, Marc; Pietzsch, Doreen; Mamat, Constantin
    Molecules (2013), 18 (), 8618-8665CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. The increasing application of positron emission tomog. (PET) in nuclear medicine has stimulated the extensive development of a multitude of novel and versatile bioorthogonal conjugation techniques esp. for the radiolabeling of biol. active high mol. wt. compds. like peptides, proteins or antibodies. Taking into consideration that the introduction of fluorine-18 (t1/2 = 109.8 min) proceeds under harsh conditions, radiolabeling of these biol. active mols. represents an outstanding challenge and is of enormous interest. Special attention has to be paid to the method of 18F-introduction. It should proceed in a regioselective manner under mild physiol. conditions, in an acceptable time span, with high yields and high specific activities. For these reasons and due to the high no. of functional groups found in these compds., a specific labeling procedure has to be developed for every bioactive macromol. Bioorthogonal strategies including the Cu-assisted Huisgen cycloaddn. and its copper-free click variant, both Staudinger Ligations or the tetrazine-click reaction have been successfully applied and represent valuable alternatives for the selective introduction of fluorine-18 to overcome the afore mentioned obstacles. This comprehensive review deals with the progress and illustrates the latest developments in the field of bioorthogonal labeling with the focus on the prepn. of radiofluorinated building blocks and tracers for mol. imaging.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ert7nI&md5=2c162751f76f760e57080404678e3d8b
  38. 38
    Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T. A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging Science 2011, 334, 639– 642
    Google Scholar
    38
    A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging
    Lee, Eunsung; Kamlet, Adam S.; Powers, David C.; Neumann, Constanze N.; Boursalian, Gregory B.; Furuya, Takeru; Choi, Daniel C.; Hooker, Jacob M.; Ritter, Tobias
    Science (Washington, DC, United States) (2011), 334 (6056), 639-642CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    The unnatural isotope fluorine-18 (18F) is used as a positron emitter in mol. imaging. Currently, many potentially useful 18F-labeled probe mols. are inaccessible for imaging because no fluorination chem. is available to make them. The 110-min half-life of 18F requires rapid syntheses for which [18F]fluoride is the preferred source of fluorine because of its practical access and suitable isotope enrichment. However, conventional [18F]fluoride chem. has been limited to nucleophilic fluorination reactions. We report the development of a palladium-based electrophilic fluorination reagent derived from fluoride and its application to the synthesis of arom. 18F-labeled mols. via late-stage fluorination. Late-stage fluorination enables the synthesis of conventionally unavailable positron emission tomog. (PET) tracers for anticipated applications in pharmaceutical development as well as preclin. and clin. PET imaging.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyqu7vL&md5=ede2fa164d6ce80035e5482966b5b57e
  39. 39
    Lee, E.; Hooker, J. M.; Ritter, T. Nickel-Mediated Oxidative Fluorination for PET with Aqueous [18F] Fluoride J. Am. Chem. Soc. 2012, 134, 17456– 17458
    Google Scholar
    There is no corresponding record for this reference.
  40. 40
    Kamlet, A. S.; Neumann, C. N.; Lee, E.; Carlin, S. M.; Moseley, C. K.; Stephenson, N.; Hooker, J. M.; Ritter, T. Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation PLoS One 2013, 8e59187
    Google Scholar
    There is no corresponding record for this reference.
  41. 41
    Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.; Groves, J. T. Late Stage Benzylic C–H Fluorination with [18F]Fluoride for PET Imaging J. Am. Chem. Soc. 2014, 136, 6842– 6845
    Google Scholar
    There is no corresponding record for this reference.
  42. 42
    Ren, H.; Wey, H.-Y.; Strebl, M.; Neelamegam, R.; Ritter, T.; Hooker, J. M. Synthesis and Imaging Validation of [18F]MDL100907 Enabled by Ni-Mediated Fluorination ACS Chem. Neurosci. 2014, 5, 611– 615
    Google Scholar
    42
    Synthesis and Imaging Validation of [18F]MDL100907 Enabled by Ni-Mediated Fluorination
    Ren, Hong; Wey, Hsiao-Ying; Strebl, Martin; Neelamegam, Ramesh; Ritter, Tobias; Hooker, Jacob M.
    ACS Chemical Neuroscience (2014), 5 (7), 611-615CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Several voids exist in reliable positron emission tomog. (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clin. research. Herein we address an unmet need in 5HT2a imaging using innovative chem. We report a scalable and robust synthesis of [18F]MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [18F]fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [18F]MDL100907. Using the new synthetic strategy and optimized procedure, [18F]MDL100907 was evaluated against [11C]MDL100907 for reliability to quantify 5HT2a in the nonhuman primate brain and was found to be superior based on a single scan anal. using the same nonhuman primate. The use of this new 5HT2a radiotracer will afford clin. neuroscience research the ability to distinguish 5HT2a receptor abnormalities binding between healthy subjects and patients even when group differences are small.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXot1yiu7g%253D&md5=067d3790608ae9f0cbe0c8d14a727651
  43. 43
    Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings Adv. Drug Delivery Rev. 2001, 46, 3– 26
    Google Scholar
    43
    Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
    Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
    Advanced Drug Delivery Reviews (2001), 46 (1-3), 3-26CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)
    A review with 50 refs. Exptl. and computational approaches to est. soly. and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the mol. wt. (MWT) is greater than 500 and the calcd. Log P (CLogP) is greater than 5 (or MlogP >4.15). Computational methodol. for the rule-based Moriguchi Log P (MLogP) calcn. is described. Turbidimetric soly. measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric soly. than leads in the pre-HTS era. In the development setting, soly. calcns. focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with exptl. thermodn. soly. measurements.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXitVOhs7o%253D&md5=c60bb89da68f051c0ee7ac4c0468a0e4
  44. 44
    Ryu, Y. H.; Liow, J.-S.; Zoghbi, S.; Fujita, M.; Collins, J.; Tipre, D.; Sangare, J.; Hong, J.; Pike, V. W.; Innis, R. B. Disulfiram Inhibits Defluorination of (18)F-FCWAY, Reduces Bone Radioactivity, and Enhances Visualization of Radioligand Binding to Serotonin 5-HT1A Receptors in Human Brain J. Nucl. Med. 2007, 48, 1154– 1161
    Google Scholar
    There is no corresponding record for this reference.
  45. 45
    Laruelle, M.; Slifstein, M.; Huang, Y. Positron Emission Tomography: Imaging and Quantification of Neurotransporter Availability Methods 2002, 27, 287– 299
    Google Scholar
    45
    Positron emission tomography: imaging and quantification of neurotransporter availability
    Laruelle, Marc; Slifstein, Mark; Huang, Yiyun
    Methods (San Diego, CA, United States) (2002), 27 (3), 287-299CODEN: MTHDE9; ISSN:1046-2023. (Elsevier Science)
    A review. Over the last decade, a large no. of radiotracers have been developed to image and quantify transporter availability with positron emission tomog. (PET) or single-photon emission computed tomog. (SPECT). Radiotracers suitable to image dopamine transporters (DATs) and serotonin transporters (SERTs) have been the object of most efforts. Following a brief overview of DAT and SERT radiotracers that have been demonstrated to be suitable for quant. anal. in vivo, this article describes the principal methods that have been used for the anal. of these data. Kinetic modeling is the most direct implementation of the compartment models, but with some tracers accurate input function measurement and good compartment configuration identification can be difficult to obtain. Other methods were designed to overcome some particular vulnerability to error of classic kinetic modeling, but introduced new vulnerabilities in the process. Ref. region methods obviate the need for arterial plasma measurement, but are not as robust to violations of the underlying modeling assumptions as methods using the arterial input function. Graphical methods give ests. of distribution vols. without the requirement of compartment model specification, but provide a biased estimator in the presence of statistical noise. True equil. methods are quite robust, but their use is limited to expts. with tracers that are suitable for const. infusion. In conclusion, no universally "best" method is applicable to all neurotransporter imaging studies, and careful evaluation of model-based methods is required for each radiotracer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmtFWhs74%253D&md5=1ec923e982f1769d80fd74b68d7b05ed
  46. 46
    NIMH Psychoactive Drug Screening Program. http://pdsp.med.unc.edu/ (accessed Jun 17, 2014) .
    Google Scholar
    There is no corresponding record for this reference.
  47. 47
    Hooker, J. M.; Kim, S. W.; Reibel, A. T.; Alexoff, D.; Xu, Y.; Shea, C. Evaluation of [11C]Metergoline as a PET Radiotracer for 5HTR in Nonhuman Primates Bioorg. Med. Chem. 2010, 18, 7739– 7745
    Google Scholar
    There is no corresponding record for this reference.
  48. 48
    Patel, S.; Hamill, T.; Hostetler, E.; Burns, H. D.; Gibson, R. E. An in Vitro Assay for Predicting Successful Imaging Radiotracers Mol. Imaging Biol. 2003, 5, 65– 71
    Google Scholar
    48
    An in vitro assay for predicting successful imaging radiotracers
    Patel Shil; Hamill Terence; Hostetler Eric; Burns H Donald; Gibson Raymond E
    Molecular imaging and biology (2003), 5 (2), 65-71 ISSN:1536-1632.
    PURPOSE: To develop an in vitro binding assay able to predict whether a radiolabel is likely to be a useful clinical tracer for positron emission tomography (PET). PROCEDURES: Rodent and rhesus brain sections were incubated with radioligands, most of which are tritiated or iodinated versions of known clinical PET radiotracers, and assayed for binding to brain receptors for a 20-minute period using a no-wash protocol (n=>/=3). RESULTS: Radiolabeled flumazenil (RO-151788), WAY100635, N-methylscopolamine, N-methylspiperone, raclopride, citalopram, (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), paroxetine, and 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-flurobenzamido]ethyl]piperazine (MPPF) were assessed for binding to either rhesus caudate putamen, and/or frontal cortex, or rat whole brain sections. Specific binding for these compounds ranged from 0 to 94% by 20 minutes. Those with %-specific binding less than 10% have also been shown to not be effective as in vivo PET radiotracers. In addition, successful PET radiotracers incubated in tissue sections with target receptor either absent or present in low density behaved poorly in this assay, as expected, as did radiolabels previously shown to possess high non-specific binding. CONCLUSIONS: An in vitro binding assay using rodent and rhesus brain sections has been developed that, within the currently assayed radiotracers, is able to rapidly predict whether a radiolabeled compound is a useful clinical PET radiotracer. This method suggests significant potential for the rapid in vitro evaluation of potential in vivo PET radiotracers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3svktFGmsQ%253D%253D&md5=4fe5e7e7ebdd730cad9a149782f7b0eb
  49. 49
    Barth, V.; Need, A. Identifying Novel Radiotracers for PET Imaging of the Brain: Application of LC-MS/MS to Tracer Identification ACS Chem. Neurosci. 2014,  DOI: 10.1021/cn500072r
    Google Scholar
    There is no corresponding record for this reference.
  50. 50
    Tournier, N.; Saba, W.; Cisternino, S.; Peyronneau, M.-A.; Damont, A.; Goutal, S.; Dubois, A.; Dollé, F.; Scherrmann, J.-M.; Valette, H.; Kuhnast, B.; Bottlaender, M. Effects of Selected OATP And/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide AAPS J. 2013, 15, 1082– 1090
    Google Scholar
    There is no corresponding record for this reference.
  51. 51
    Syvänen, S.; Lindhe, Ö.; Palner, M.; Kornum, B. R.; Rahman, O.; Långström, B.; Knudsen, G. M.; Hammarlund-Udenaes, M. Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport Drug Metab. Dispos. 2009, 37, 635– 643
    Google Scholar
    There is no corresponding record for this reference.
  52. 52
    Varnäs, K.; Varrone, A.; Farde, L. Modeling of PET Data in CNS Drug Discovery and Development J. Pharmacokinet. Pharmacodyn. 2013, 40, 267– 279
    Google Scholar
    52
    Modeling of PET data in CNS drug discovery and development
    Varnas Katarina; Varrone Andrea; Farde Lars
    Journal of pharmacokinetics and pharmacodynamics (2013), 40 (3), 267-79 ISSN:.
    Positron emission tomography (PET) is increasingly used in drug discovery and development for evaluation of CNS drug disposition and for studies of disease biomarkers to monitor drug effects on brain pathology. The quantitative analysis of PET data is based on kinetic modeling of radioactivity concentrations in plasma and brain tissue compartments. A number of quantitative methods of analysis have been developed that allow the determination of parameters describing drug pharmacokinetics and interaction with target binding sites in the brain. The optimal method of quantification depends on the properties of the radiolabeled drug or radioligand and the binding site studied. We here review the most frequently used methods for quantification of PET data in relation to CNS drug discovery and development. The utility of PET kinetic modeling in the development of novel CNS drugs is illustrated by examples from studies of the brain kinetic properties of radiolabeled drug molecules.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3snisVajtQ%253D%253D&md5=8afb967eb7584f68ed62fa08f7907a74
  53. 53
    Kuntner, C. Kinetic Modeling in Preclinical Positron Emission Tomography Z. Med. Phys. 2014,  DOI: 10.1016/j.zemedi.2014.02.003
    Google Scholar
    There is no corresponding record for this reference.

Cited By

ARTICLE SECTIONS
Jump To

This article is cited by 102 publications.

  1. Ping Bai, Frederick A. Bagdasarian, Yulong Xu, Yanli Wang, Yongle Wang, Ashley Gomm, Yanting Zhou, Rui Wu, Hsiao-Ying Wey, Rudolph E. Tanzi, Can Zhang, Yu Lan, Changning Wang. Molecular Imaging of Alzheimer’s Disease-Related Sigma-1 Receptor in the Brain via a Novel Ru-Mediated Aromatic 18F-deoxyfluorination Probe. Journal of Medicinal Chemistry 2024, 67 (8) , 6207-6217. https://doi.org/10.1021/acs.jmedchem.3c02178
  2. Yiming Xu, Yulong Xu, Savannah Biby, Baljit Kaur, Yan Liu, Frederick Andrew Bagdasarian, Hsiao-Ying Wey, Rudolph Tanzi, Can Zhang, Changning Wang, Shijun Zhang. Design and Discovery of Novel NLRP3 Inhibitors and PET Imaging Radiotracers Based on a 1,2,3-Triazole-Bearing Scaffold. Journal of Medicinal Chemistry 2024, 67 (1) , 555-571. https://doi.org/10.1021/acs.jmedchem.3c01782
  3. Mausam Kalita, Jun Hyung Park, Renesmee Chenting Kuo, Samira Hayee, Sara Marsango, Valentina Straniero, Israt S. Alam, Angelie Rivera-Rodriguez, Mallesh Pandrala, Mackenzie L. Carlson, Samantha T. Reyes, Isaac M. Jackson, Lorenzo Suigo, Audrey Luo, Sydney C. Nagy, Ermanno Valoti, Graeme Milligan, Frezghi Habte, Bin Shen, Michelle L. James. PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84. JACS Au 2023, 3 (12) , 3297-3310. https://doi.org/10.1021/jacsau.3c00435
  4. Nashaat Turkman, Sulan Xu, Chun-Han Huang, Christopher Eyermann, Julia Salino, Palwasha Khan. High-Contrast PET Imaging with [18F]NT160, a Class-IIa Histone Deacetylase Probe for In Vivo Imaging of Epigenetic Machinery in the Central Nervous System. Journal of Medicinal Chemistry 2023, 66 (8) , 5611-5621. https://doi.org/10.1021/acs.jmedchem.2c02064
  5. Uzair S. Ismailani, Ariel Buchler, Nicole MacMullin, Faduma Abdirahman, Myriam Adi, Benjamin H. Rotstein. Synthesis and Evaluation of [11C]MCC950 for Imaging NLRP3-Mediated Inflammation in Atherosclerosis. Molecular Pharmaceutics 2023, 20 (3) , 1709-1716. https://doi.org/10.1021/acs.molpharmaceut.2c00915
  6. Nicole D. Bartolo, Niall Mortimer, Mariah A. Manter, Nicholas Sanchez, Misha Riley, Tiernan T. O’Malley, Jacob M. Hooker. Identification and Prioritization of PET Neuroimaging Targets for Microglial Phenotypes Associated with Microglial Activity in Alzheimer’s Disease. ACS Chemical Neuroscience 2022, 13 (24) , 3641-3660. https://doi.org/10.1021/acschemneuro.2c00607
  7. Erin L. ColeLindsey R. Drake. POSITRON EMISSION TOMOGRAPHY NEUROIMAGING IN DRUG DISCOVERY AND DEVELOPMENT. , 61-90. https://doi.org/10.1021/mc-2022-vol57.ch03
  8. Isaac M. Jackson, E. William Webb, Peter J.H. Scott, Michelle L. James. In Silico Approaches for Addressing Challenges in CNS Radiopharmaceutical Design. ACS Chemical Neuroscience 2022, 13 (12) , 1675-1683. https://doi.org/10.1021/acschemneuro.2c00269
  9. Ping Bai, Yu Lan, Debasis Patnaik, Hao Wang, Yan Liu, Zude Chen, Gengyang Yuan, Sepideh Afshar, Robin Striar, Julia S. Zagaroli, Darcy R. Tocci, Amelia G. Langan, Stephen J. Haggarty, Changning Wang. Design, Synthesis, and Evaluation of Thienodiazepine Derivatives as Positron Emission Tomography Imaging Probes for Bromodomain and Extra-Terminal Domain Family Proteins. Journal of Medicinal Chemistry 2021, 64 (19) , 14745-14756. https://doi.org/10.1021/acs.jmedchem.1c01323
  10. Min Guo, Abolghasem Bakhoda, Zhan-Guo Gao, Joseph M. Ramsey, Yang Li, Kelly A. O’Conor, Andrew C. Kelleher, Seth M. Eisenberg, Yeona Kang, Xuefeng Yan, Cameron Javdan, Joanna S. Fowler, Kenner C. Rice, Jacob M. Hooker, Kenneth A. Jacobson, Sung Won Kim, Nora D. Volkow. Discovery of Highly Potent Adenosine A1 Receptor Agonists: Targeting Positron Emission Tomography Probes. ACS Chemical Neuroscience 2021, 12 (18) , 3410-3417. https://doi.org/10.1021/acschemneuro.1c00397
  11. Antonio Giordani, Maria Cristina Menziani, Rosa Maria Moresco, Mario Matarrese, Marco Paolino, Mario Saletti, Germano Giuliani, Maurizio Anzini, Andrea Cappelli. Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria. Journal of Medicinal Chemistry 2021, 64 (14) , 9649-9676. https://doi.org/10.1021/acs.jmedchem.1c00379
  12. Christian B. M. Poulie, Anders A. Jensen, Adam L. Halberstadt, Jesper L. Kristensen. DARK Classics in Chemical Neuroscience: NBOMes. ACS Chemical Neuroscience 2020, 11 (23) , 3860-3869. https://doi.org/10.1021/acschemneuro.9b00528
  13. Elina Tampio L’Estrade, Mengfei Xiong, Vladimir Shalgunov, Fraser G. Edgar, Balázs Volk, Simone L. Baerentzen, Mikael Palner, Maria Erlandsson, Tomas Ohlsson, Gitte M. Knudsen, Matthias M. Herth. Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers: [18F]ENL09 and [18F]ENL10. ACS Chemical Neuroscience 2019, 10 (9) , 3961-3968. https://doi.org/10.1021/acschemneuro.9b00132
  14. Alexandra R. Sowa, Allen F. Brooks, Xia Shao, Bradford D. Henderson, Philip Sherman, Janna Arteaga, Jenelle Stauff, Adam C. Lee, Robert A. Koeppe, Peter J. H. Scott, Michael R. Kilbourn. Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1. ACS Chemical Neuroscience 2018, 9 (11) , 2767-2773. https://doi.org/10.1021/acschemneuro.8b00183
  15. Vadim Bernard-Gauthier, Justin J. Bailey, Andrew V. Mossine, Simon Lindner, Lena Vomacka, Arturo Aliaga, Xia Shao, Carole A. Quesada, Phillip Sherman, Anne Mahringer, Alexey Kostikov, Marilyn Grand’Maison, Pedro Rosa-Neto, Jean-Paul Soucy, Alexander Thiel, David R. Kaplan, Gert Fricker, Björn Wängler, Peter Bartenstein, Ralf Schirrmacher, and Peter J. H. Scott . A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human. Journal of Medicinal Chemistry 2017, 60 (16) , 6897-6910. https://doi.org/10.1021/acs.jmedchem.7b00396
  16. Martin G. Strebl, Changning Wang, Frederick A. Schroeder, Michael S. Placzek, Hsiao-Ying Wey, Genevieve C. Van de Bittner, Ramesh Neelamegam, and Jacob M. Hooker . Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance. ACS Chemical Neuroscience 2016, 7 (5) , 528-533. https://doi.org/10.1021/acschemneuro.5b00297
  17. Jiefang He, Célia S. Bonnet, Svetlana V. Eliseeva, Sara Lacerda, Thomas Chauvin, Pascal Retailleau, Frederic Szeremeta, Bernard Badet, Stéphane Petoud, Éva Tóth, and Philippe Durand . Prototypes of Lanthanide(III) Agents Responsive to Enzymatic Activities in Three Complementary Imaging Modalities: Visible/Near-Infrared Luminescence, PARACEST-, and T1-MRI. Journal of the American Chemical Society 2016, 138 (9) , 2913-2916. https://doi.org/10.1021/jacs.5b12084
  18. Eric P. Gillis, Kyle J. Eastman, Matthew D. Hill, David J. Donnelly, and Nicholas A. Meanwell . Applications of Fluorine in Medicinal Chemistry. Journal of Medicinal Chemistry 2015, 58 (21) , 8315-8359. https://doi.org/10.1021/acs.jmedchem.5b00258
  19. Ida Vang Andersen, Natasha Shalina Rajani Bidesi, Vladimir Shalgunov, Jesper Tranekjær Jørgensen, Tobias Gustavsson, Kristian Strømgaard, Andreas T. Ingemann Jensen, Andreas Kjær, Matthias M. Herth. Investigation of imaging the somatostatin receptor by opening the blood-brain barrier with melittin – A feasibility study using positron emission tomography and [64Cu]Cu-DOTATATE. Nuclear Medicine and Biology 2024, 132-133 , 108905. https://doi.org/10.1016/j.nucmedbio.2024.108905
  20. Shahnaz Saednia, Saeed Emami, Masoud Moslehi, Seyed Jalal Hosseinimehr. Insights into the development of 99mTc-radioligands for serotonergic receptors imaging: Synthesis, labeling, In vitro, and In vivo studies. European Journal of Medicinal Chemistry 2024, 270 , 116349. https://doi.org/10.1016/j.ejmech.2024.116349
  21. Swen Humpert, Daniela Schneider, Markus Lang, Annette Schulze, Felix Neumaier, Marcus Holschbach, Dirk Bier, Bernd Neumaier. Radiosynthesis and In Vitro Evaluation of [11C]tozadenant as Adenosine A2A Receptor Radioligand. Molecules 2024, 29 (5) , 1089. https://doi.org/10.3390/molecules29051089
  22. Yingfang He, Stefanie D. Krämer, Uwe Grether, Matthias B. Wittwer, Ludovic Collin, Bernd Kuhn, Andreas Topp, Dominik Heer, Fionn O’Hara, Michael Honer, Anto Pavlovic, Hans Richter, Martin Ritter, Didier Rombach, Claudia Keller, Luca Gobbi, Linjing Mu. Identification of ( R )-[ 18 F]YH134 for Monoacylglycerol Lipase Neuroimaging and Exploration of Its Use for Central Nervous System and Peripheral Drug Development. Journal of Nuclear Medicine 2024, 65 (2) , 300-305. https://doi.org/10.2967/jnumed.123.266426
  23. Drew R. DeBay, Kimberly D. Brewer. Combined PET/MR: Where Anatomical Imaging Meets Cellular Function. 2024, 391-408. https://doi.org/10.1007/978-1-0716-3499-8_22
  24. Marlon Millard, Jonas Kilian, Marius Ozenil, Mariella Mogeritsch, Verena Schwingenschlögl-Maisetschläger, Wolfgang Holzer, Marcus Hacker, Thierry Langer, Verena Pichler. Design, synthesis and preclinical evaluation of muscarine receptor antagonists via a scaffold-hopping approach. European Journal of Medicinal Chemistry 2023, 262 , 115891. https://doi.org/10.1016/j.ejmech.2023.115891
  25. Yingbo Li, Junfeng Wang. Site‐specifically radiolabeled nanobodies for imaging blood‐brain barrier penetration and targeting in the brain. Journal of Labelled Compounds and Radiopharmaceuticals 2023, 66 (14) , 444-451. https://doi.org/10.1002/jlcr.4069
  26. Behnaz Akbari, Bertrand Russell Huber, Janet Hope Sherman. Unlocking the Hidden Depths: Multi-Modal Integration of Imaging Mass Spectrometry-Based and Molecular Imaging Techniques. Critical Reviews in Analytical Chemistry 2023, 17 , 1-30. https://doi.org/10.1080/10408347.2023.2266838
  27. Anne-Claire Dupont, Nicolas Arlicot, Johnny Vercouillie, Sophie Serrière, Serge Maia, Frédérique Bonnet-Brilhault, Maria-Joao Santiago-Ribeiro. Metabotropic Glutamate Receptor Subtype 5 Positron-Emission-Tomography Radioligands as a Tool for Central Nervous System Drug Development: Between Progress and Setbacks. Pharmaceuticals 2023, 16 (8) , 1127. https://doi.org/10.3390/ph16081127
  28. Anton Lindberg, Melissa Chassé, Cassis Varlow, Anna Pees, Neil Vasdev. Strategies for designing novel positron emission tomography (PET) radiotracers to cross the blood–brain barrier. Journal of Labelled Compounds and Radiopharmaceuticals 2023, 66 (9) , 205-221. https://doi.org/10.1002/jlcr.4019
  29. Andrea I. Luppi, Justine Y. Hansen, Ram Adapa, Robin L. Carhart-Harris, Leor Roseman, Christopher Timmermann, Daniel Golkowski, Andreas Ranft, Rüdiger Ilg, Denis Jordan, Vincent Bonhomme, Audrey Vanhaudenhuyse, Athena Demertzi, Oceane Jaquet, Mohamed Ali Bahri, Naji L. N. Alnagger, Paolo Cardone, Alexander R. D. Peattie, Anne E. Manktelow, Draulio B. de Araujo, Stefano L. Sensi, Adrian M. Owen, Lorina Naci, David K. Menon, Bratislav Misic, Emmanuel A. Stamatakis. In vivo mapping of pharmacologically induced functional reorganization onto the human brain’s neurotransmitter landscape. Science Advances 2023, 9 (24) https://doi.org/10.1126/sciadv.adf8332
  30. Priya Singh, Deepika Singh, Pooja Srivastava, Gauri Mishra, Anjani K. Tiwari. Evaluation of advanced, pathophysiologic new targets for imaging of CNS. Drug Development Research 2023, 84 (3) , 418-447. https://doi.org/10.1002/ddr.22040
  31. Felix Neumaier, Boris D. Zlatopolskiy, Bernd Neumaier. Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas. Molecules 2023, 28 (7) , 2890. https://doi.org/10.3390/molecules28072890
  32. Vladimir Shalgunov, Sara Lopes van den Broek, Ida Vang Andersen, Rocío García Vázquez, Nakul Ravi Raval, Mikael Palner, Yuki Mori, Gabriela Schäfer, Barbara Herrmann, Hannes Mikula, Natalie Beschorner, Maiken Nedergaard, Stina Syvänen, Matthias Barz, Gitte Moos Knudsen, Umberto Maria Battisti, Matthias Manfred Herth. Pretargeted imaging beyond the blood–brain barrier. RSC Medicinal Chemistry 2023, 14 (3) , 444-453. https://doi.org/10.1039/D2MD00360K
  33. Shuhei Ikeda, Yuichi Kajita, Maki Miyamoto, Kouta Matsumiya, Tsuyoshi Ishii, Toshiya Nishi, Sean C. Gay, Weston Lane, Cristian C. Constantinescu, David Alagille, Caroline Papin, Gilles Tamagnan, Takanobu Kuroita, Tatsuki Koike. Design and synthesis of aryl-piperidine derivatives as potent and selective PET tracers for cholesterol 24-hydroxylase (CH24H). European Journal of Medicinal Chemistry 2022, 240 , 114612. https://doi.org/10.1016/j.ejmech.2022.114612
  34. Ping Bai, Liu Yan, Frederick A. Bagdasarian, Moses Q. Wilks, Hsiao-Ying Wey, Changning Wang. A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain. Chemical Communications 2022, 58 (69) , 9654-9657. https://doi.org/10.1039/D2CC03785H
  35. Enza Di Gregorio, Mariangela Boccalon, Chiara Furlan, Eliana Gianolio, Attila Bényei, Silvio Aime, Zsolt Baranyai, Giuseppe Ferrauto. Studies of the hydrophobic interaction between a pyrene-containing dye and a tetra-aza macrocyclic gadolinium complex. Inorganic Chemistry Frontiers 2022, 9 (14) , 3494-3504. https://doi.org/10.1039/D2QI00596D
  36. Ping Bai, Yan Liu, Yulong Xu, Robin Striar, Gengyang Yuan, Sepideh Afshar, Amelia G. Langan, Anna K. Rattray, Changning Wang. Synthesis and characterization of a new Positron emission tomography probe for orexin 2 receptors neuroimaging. Bioorganic Chemistry 2022, 123 , 105779. https://doi.org/10.1016/j.bioorg.2022.105779
  37. E. Johanna L. Stéen, Danielle J. Vugts, Albert D. Windhorst. The Application of in silico Methods for Prediction of Blood-Brain Barrier Permeability of Small Molecule PET Tracers. Frontiers in Nuclear Medicine 2022, 2 https://doi.org/10.3389/fnume.2022.853475
  38. Joanna S. Fowler, Nora D. Volkow. Molecular Imaging: Positron Emission Tomography. 2022, 3297-3321. https://doi.org/10.1007/978-3-030-88832-9_149
  39. Dileep Kumar, Ramesh Neelamegam, Thomas Chaly. Radiosynthesis and in Vivo Imaging of Vegfr2 Pet Ligand [11c]Btfp. SSRN Electronic Journal 2022, 17 https://doi.org/10.2139/ssrn.4058983
  40. Shuhei Ikeda, Yuichi Kajita, Maki Miyamoto, Kouta Matsumiya, Tsuyoshi Ishii, Toshiya Nishi, Sean C. Gay, Weston Lane, Cristian C. Constantinescu, David Alagille, Caroline Papin, Gilles Tamagnan, Takanobu Kuroita, Tatsuki Koike. Design and Synthesis of Aryl-Piperidine Derivatives as Potent and Selective PET Tracers for Cholesterol 24-Hydroxylase (CH24H). SSRN Electronic Journal 2022, 78 https://doi.org/10.2139/ssrn.4137501
  41. Dagmawi Yitbarek, Gashaw Getaneh Dagnaw. Application of Advanced Imaging Modalities in Veterinary Medicine: A Review. Veterinary Medicine: Research and Reports 2022, Volume 13 , 117-130. https://doi.org/10.2147/VMRR.S367040
  42. Ramesh Neelamegam, Thomas Chaly, J.S. Dileep Kumar. Radiosynthesis and in vivo imaging of [11C]BTFP, a potent inhibitor of VEGFR2. Results in Chemistry 2022, 4 , 100381. https://doi.org/10.1016/j.rechem.2022.100381
  43. Benedetta Bodini, Matteo Tonietto, Laura Airas, Bruno Stankoff. Positron emission tomography in multiple sclerosis — straight to the target. Nature Reviews Neurology 2021, 17 (11) , 663-675. https://doi.org/10.1038/s41582-021-00537-1
  44. Sandrine M. Hell, Claudio F. Meyer, Sebastiano Ortalli, Jeroen B. I. Sap, Xuanxiao Chen, Véronique Gouverneur. Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond. Chemical Science 2021, 12 (36) , 12149-12155. https://doi.org/10.1039/D1SC03421A
  45. Andy Welch, Adriana A. S. Tavares, Sally Pimlott, Andrew Sutherland. PET and SPECT in Drug Development. 2021, 1-18. https://doi.org/10.1002/0471266949.bmc254.pub2
  46. Noeen Malik, Rick Kornelsen, Siobhan McCormick, Nadine Colpo, Helen Merkens, Shreya Bendre, Francois Benard, Vesna Sossi, Ralf Schirrmacher, Paul Schaffer. Development and biological evaluation of[18F]FMN3PA & [18F]FMN3PU for leucine-rich repeat kinase 2 (LRRK2) in vivo PET imaging. European Journal of Medicinal Chemistry 2021, 211 , 113005. https://doi.org/10.1016/j.ejmech.2020.113005
  47. Thu Hang Lai, Magali Toussaint, Rodrigo Teodoro, Sladjana Dukić-Stefanović, Mathias Kranz, Winnie Deuther-Conrad, Rareş-Petru Moldovan, Peter Brust. Synthesis and Biological Evaluation of a Novel 18F-Labeled Radiotracer for PET Imaging of the Adenosine A2A Receptor. International Journal of Molecular Sciences 2021, 22 (3) , 1182. https://doi.org/10.3390/ijms22031182
  48. Caitlin Jie, Valerie Treyer, Roger Schibli, Linjing Mu. Tauvid™: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer’s Disease. Pharmaceuticals 2021, 14 (2) , 110. https://doi.org/10.3390/ph14020110
  49. Linjing Mu, Simon M. Ametamey. Current Radioligands for the PET Imaging of Metabotropic Glutamate Receptors. 2021, 427-481. https://doi.org/10.1007/978-3-030-53176-8_13
  50. Bastian Zinnhardt, Cristina Barca, Claudia Foray, Inga B. Fricke, Thomas Viel, Alexandra Winkeler, Albert D. Windhorst, Andreas H. Jacobs. Neuroinflammation: From Target Selection to Preclinical and Clinical Studies. 2021, 567-592. https://doi.org/10.1007/978-3-030-53176-8_17
  51. Ralf Schirrmacher, Vadim Bernard-Gauthier, Carolin Jaworski, Carmen Wängler, Björn Wängler, Justin Bailey. Toward Imaging Tropomyosin Receptor Kinase (Trk) with Positron Emission Tomography. 2021, 1041-1059. https://doi.org/10.1007/978-3-030-53176-8_31
  52. Lilja B. Solnes, Andreas H. Jacobs, Jennifer M. Coughlin, Yong Du, Reema Goel, Dima A. Hammoud, Martin G. Pomper. Central Nervous System Molecular Imaging. 2021, 1261-1285. https://doi.org/10.1016/B978-0-12-816386-3.00088-0
  53. Michael R. Kilbourn. Targeted Diagnostic Radiopharmaceuticals: Design Options for Small‐Molecule Radiotracers. 2020, 1-21. https://doi.org/10.1002/9781119500575.ch1
  54. David J. Donnelly,. PET Imaging in Drug Discovery and Development. 2020, 703-725. https://doi.org/10.1002/9781119500575.ch22
  55. Krishna Kanta Ghosh, Parasuraman Padmanabhan, Chang-Tong Yang, Sachin Mishra, Christer Halldin, Balázs Gulyás. Dealing with PET radiometabolites. EJNMMI Research 2020, 10 (1) https://doi.org/10.1186/s13550-020-00692-4
  56. Marius Ozenil, Katharina Pacher, Theresa Balber, Chrysoula Vraka, Alexander Roller, Wolfgang Holzer, Helmut Spreitzer, Markus Mitterhauser, Wolfgang Wadsak, Marcus Hacker, Verena Pichler. Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers. European Journal of Medicinal Chemistry 2020, 204 , 112623. https://doi.org/10.1016/j.ejmech.2020.112623
  57. Robert C. Shaw, Gilles D. Tamagnan, Adriana Alexandre S. Tavares. Rapidly (and Successfully) Translating Novel Brain Radiotracers From Animal Research Into Clinical Use. Frontiers in Neuroscience 2020, 14 https://doi.org/10.3389/fnins.2020.00871
  58. Elina T. L'Estrade, Maria Erlandsson, Fraser G. Edgar, Tomas Ohlsson, Gitte M. Knudsen, Matthias M. Herth. Towards selective CNS PET imaging of the 5-HT7 receptor system: Past, present and future. Neuropharmacology 2020, 172 , 107830. https://doi.org/10.1016/j.neuropharm.2019.107830
  59. Brendan J. Evans, Andrew T. King, Andrew Katsifis, Lidia Matesic, Joanne F. Jamie. Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals. Molecules 2020, 25 (10) , 2314. https://doi.org/10.3390/molecules25102314
  60. Ping Bai, Sha Bai, Michael S. Placzek, Xiaoxia Lu, Stephanie A. Fiedler, Brenda Ntaganda, Hsiao-Ying Wey, Changning Wang. A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging. Molecules 2020, 25 (5) , 1018. https://doi.org/10.3390/molecules25051018
  61. Cornelius K. Donat, Henrik H. Hansen, Hanne D. Hansen, Ronnie C. Mease, Andrew G. Horti, Martin G. Pomper, Elina T. L’Estrade, Matthias M. Herth, Dan Peters, Gitte M. Knudsen, Jens D. Mikkelsen. In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors. Molecules 2020, 25 (6) , 1425. https://doi.org/10.3390/molecules25061425
  62. Elina T. L 'Estrade, Vladimir Shalgunov, Fraser G. Edgar, Martin G. Strebl‐Bantillo, Mengfei Xiong, François Crestey, Ramesh Neelamegam, Agnete Dyssegaard, Szabolcs Lehel, Maria Erlandsson, Tomas Ohlsson, Jacob M. Hooker, Gitte M. Knudsen, Matthias M. Herth, Hanne D. Hansen. Radiosynthesis and preclinical evaluation of [ 11 C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT 7 receptors. Journal of Labelled Compounds and Radiopharmaceuticals 2020, 63 (2) , 46-55. https://doi.org/10.1002/jlcr.3808
  63. Stuart P. McCluskey, Christophe Plisson, Eugenii A. Rabiner, Oliver Howes. Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development. European Journal of Nuclear Medicine and Molecular Imaging 2020, 47 (2) , 451-489. https://doi.org/10.1007/s00259-019-04488-0
  64. Bright Chukwunwike Uzuegbunam, Damiano Librizzi, Behrooz Hooshyar Yousefi. PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape. Molecules 2020, 25 (4) , 977. https://doi.org/10.3390/molecules25040977
  65. Antony D. Gee, Matthias M. Herth, Michelle L. James, Aruna Korde, Peter J. H. Scott, Neil Vasdev. Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions. Molecular Imaging 2020, 19 , 153601212093639. https://doi.org/10.1177/1536012120936397
  66. Stephanie Federico, Lucia Lassiani, Giampiero Spalluto. Chemical Probes for the Adenosine Receptors. Pharmaceuticals 2019, 12 (4) , 168. https://doi.org/10.3390/ph12040168
  67. Yu Lan, Ping Bai, Zude Chen, Ramesh Neelamegam, Michael S. Placzek, Hao Wang, Stephanie A. Fiedler, Jing Yang, Gengyang Yuan, Xiying Qu, Hayden R. Schmidt, Jinchun Song, Marc D. Normandin, Chongzhao Ran, Changning Wang. Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET). Acta Pharmaceutica Sinica B 2019, 9 (6) , 1204-1215. https://doi.org/10.1016/j.apsb.2019.07.002
  68. Matthieu Colom, Benjamin Vidal, Luc Zimmer. Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?. Frontiers in Molecular Neuroscience 2019, 12 https://doi.org/10.3389/fnmol.2019.00255
  69. Youwen Xu, Zizhong Li. Imaging metabotropic glutamate receptor system: Application of positron emission tomography technology in drug development. Medicinal Research Reviews 2019, 39 (5) , 1892-1922. https://doi.org/10.1002/med.21566
  70. Koen Vermeulen, Mathilde Vandamme, Guy Bormans, Frederik Cleeren. Design and Challenges of Radiopharmaceuticals. Seminars in Nuclear Medicine 2019, 49 (5) , 339-356. https://doi.org/10.1053/j.semnuclmed.2019.07.001
  71. Jacob M. Hooker, Richard E. Carson. Human Positron Emission Tomography Neuroimaging. Annual Review of Biomedical Engineering 2019, 21 (1) , 551-581. https://doi.org/10.1146/annurev-bioeng-062117-121056
  72. Agnė Stadulytė, Carlos José Alcaide-Corral, Tashfeen Walton, Christophe Lucatelli, Adriana Alexandre S. Tavares. Analysis of PK11195 concentrations in rodent whole blood and tissue samples by rapid and reproducible chromatographic method to support target-occupancy PET studies. Journal of Chromatography B 2019, 1118-1119 , 33-39. https://doi.org/10.1016/j.jchromb.2019.04.026
  73. Vladimir Shalgunov, Aren van Waarde, Jan Booij, Martin C. Michel, Rudi A. J. O. Dierckx, Philip H. Elsinga. Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging. Medicinal Research Reviews 2019, 39 (3) , 1014-1052. https://doi.org/10.1002/med.21552
  74. Dario Doller, Paul Wes. Quality of Research Tools. 2019, 119-145. https://doi.org/10.1007/164_2019_281
  75. Chun-Ping Chang, Ho-Lien Huang, Jing-Kai Huang, Ming-Shiu Hung, Chien-Huang Wu, Jen-Shin Song, Chia-Jui Lee, Chung-Shan Yu, Kak-Shan Shia. Fluorine-18 isotope labeling for positron emission tomography imaging. Direct evidence for DBPR211 as a peripherally restricted CB1 inverse agonist. Bioorganic & Medicinal Chemistry 2019, 27 (1) , 216-223. https://doi.org/10.1016/j.bmc.2018.11.043
  76. Ying-Hwey Nai, Hiroshi Watabe. Evaluation of the Feasibility of Screening Tau Radiotracers Using an Amyloid Biomathematical Screening Methodology. Computational and Mathematical Methods in Medicine 2018, 2018 , 1-13. https://doi.org/10.1155/2018/6287913
  77. Yves P. Auberson, Emmanuelle Briard, Bettina Rudolph, Klemens Kaupmann, Paul Smith, Berndt Oberhauser. PET Imaging of T Cells: Target Identification and Feasibility Assessment. ChemMedChem 2018, 13 (15) , 1566-1579. https://doi.org/10.1002/cmdc.201800241
  78. Yinhui Li, Di Xu, Hei‐Nga Chan, Chung‐Yan Poon, See‐Lok Ho, Hung‐Wing Li, Man Shing Wong. Dual‐Modal NIR‐Fluorophore Conjugated Magnetic Nanoparticle for Imaging Amyloid‐β Species In Vivo. Small 2018, 14 (28) https://doi.org/10.1002/smll.201800901
  79. Ying‐Cheng Huang, Shiou‐Shiow Farn, Yo‐Cheng Chou, Chun‐Nan Yeh, Chi‐Wei Chang, Yi‐Hsiu Chung, Tsong‐Wen Chen, Wen‐Sheng Huang, Chung‐Shan Yu. Synthesis of para ‐[ 18 F]Fluorofenbufen Octylamide for PET Imaging of Brain Tumors. Journal of the Chinese Chemical Society 2018, 65 (6) , 780-792. https://doi.org/10.1002/jccs.201700300
  80. Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G. Patching. Efflux proteins at the blood–brain barrier: review and bioinformatics analysis. Xenobiotica 2018, 48 (5) , 506-532. https://doi.org/10.1080/00498254.2017.1328148
  81. Annette Johansen, Hanne D Hansen, Claus Svarer, Szabolcs Lehel, Sebastian Leth-Petersen, Jesper L Kristensen, Nic Gillings, Gitte M Knudsen. The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [ 11 C]Cimbi-36 labeled in two positions. Journal of Cerebral Blood Flow & Metabolism 2018, 38 (4) , 659-668. https://doi.org/10.1177/0271678X17746179
  82. Yoori Choi, Seunggyun Ha, Yun-Sang Lee, Yun Kyung Kim, Dong Soo Lee, Dong Jin Kim. Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies. Nuclear Medicine and Molecular Imaging 2018, 52 (1) , 24-30. https://doi.org/10.1007/s13139-017-0484-7
  83. Vidya Narayanaswami, Kenneth Dahl, Vadim Bernard-Gauthier, Lee Josephson, Paul Cumming, Neil Vasdev. Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO. Molecular Imaging 2018, 17 , 153601211879231. https://doi.org/10.1177/1536012118792317
  84. Andrew V. Mossine, Allen F. Brooks, Naoko Ichiishi, Katarina J. Makaravage, Melanie S. Sanford, Peter J. H. Scott. Development of Customized [18F]Fluoride Elution Techniques for the Enhancement of Copper-Mediated Late-Stage Radiofluorination. Scientific Reports 2017, 7 (1) https://doi.org/10.1038/s41598-017-00110-1
  85. Michael R. Kilbourn, Peter J.H. Scott. Is logP truly dead?. Nuclear Medicine and Biology 2017, 54 , 41-42. https://doi.org/10.1016/j.nucmedbio.2017.08.006
  86. Genevieve C. Van de Bittner, Misha M. Riley, Luxiang Cao, Janina Ehses, Scott P. Herrick, Emily L. Ricq, Hsiao-Ying Wey, Michael J. O’Neill, Zeshan Ahmed, Tracey K. Murray, Jaclyn E. Smith, Changning Wang, Frederick A. Schroeder, Mark W. Albers, Jacob M. Hooker. Nasal neuron PET imaging quantifies neuron generation and degeneration. Journal of Clinical Investigation 2017, 127 (2) , 681-694. https://doi.org/10.1172/JCI89162
  87. Norman Koglin, Andre Mueller, Andrew W. Stephens, Ludger M. Dinkelborg. How to Identify Suitable Molecular Imaging Biomarkers. 2017, 163-176. https://doi.org/10.1007/978-3-319-42202-2_10
  88. J. Mercier, L. Provins, J. Hannestad. Progress and Challenges in the Development of PET Ligands to Aid CNS Drug Discovery. 2017, 20-64. https://doi.org/10.1016/B978-0-12-409547-2.12437-0
  89. Susan Z. Lever, Kuo-Hsien Fan, John R. Lever. Tactics for preclinical validation of receptor-binding radiotracers. Nuclear Medicine and Biology 2017, 44 , 4-30. https://doi.org/10.1016/j.nucmedbio.2016.08.015
  90. Brian P. Rempel, Eric W. Price, Christopher P. Phenix. Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT. Molecular Imaging 2017, 16 , 153601211771785. https://doi.org/10.1177/1536012117717852
  91. Sally Wagner, Rodrigo Teodoro, Winnie Deuther‐Conrad, Mathias Kranz, Matthias Scheunemann, Steffen Fischer, Barbara Wenzel, Ute Egerland, Norbert Hoefgen, Jörg Steinbach, Peter Brust. Radiosynthesis and biological evaluation of the new PDE10A radioligand [ 18 F]AQ28A. Journal of Labelled Compounds and Radiopharmaceuticals 2017, 60 (1) , 36-48. https://doi.org/10.1002/jlcr.3471
  92. Kiwamu Matsuoka, Fumihiko Yasuno, Takayuki Shinkai, Toshiteru Miyasaka, Masato Takahashi, Kuniaki Kiuchi, Jun Kosaka, Makoto Inoue, Kimihiko Kichikawa, Masatoshi Hasegawa, Toshifumi Kishimoto. Test-retest reproducibility of extrastriatal binding with 123 I-FP-CIT SPECT in healthy male subjects. Psychiatry Research: Neuroimaging 2016, 258 , 10-15. https://doi.org/10.1016/j.pscychresns.2016.10.007
  93. Natascha Nebel, Simone Maschauer, Torsten Kuwert, Carsten Hocke, Olaf Prante. In Vitro and In Vivo Characterization of Selected Fluorine-18 Labeled Radioligands for PET Imaging of the Dopamine D3 Receptor. Molecules 2016, 21 (9) , 1144. https://doi.org/10.3390/molecules21091144
  94. Ying-Cheng Huang, Yu-Chia Chang, Chun-Nan Yeh, Chung-Shan Yu. Synthesis and Biological Evaluation of an 18Fluorine-Labeled COX Inhibitor—[18F]Fluorooctyl Fenbufen Amide—For Imaging of Brain Tumors. Molecules 2016, 21 (3) , 387. https://doi.org/10.3390/molecules21030387
  95. Joanna S. Fowler, Nora D. Volkow. Molecular Imaging: Positron Emission Tomography. 2016, 1-26. https://doi.org/10.1007/978-1-4614-6434-1_149-2
  96. Joanna S. Fowler, Nora D. Volkow. Molecular Imaging: Positron Emission Tomography. 2016, 2929-2954. https://doi.org/10.1007/978-1-4939-3474-4_149
  97. Mattia Riondato, William C. Eckelman. Radiopharmaceuticals. 2016, 31-57. https://doi.org/10.1007/978-3-319-31614-7_4
  98. Benjamin H. Rotstein, Steven H. Liang, Michael S. Placzek, Jacob M. Hooker, Antony D. Gee, Frédéric Dollé, Alan A. Wilson, Neil Vasdev. 11 CO bonds made easily for positron emission tomography radiopharmaceuticals. Chemical Society Reviews 2016, 45 (17) , 4708-4726. https://doi.org/10.1039/C6CS00310A
  99. Michael S. Placzek, Wenjun Zhao, Hsiao-Ying Wey, Thomas M. Morin, Jacob M. Hooker. PET Neurochemical Imaging Modes. Seminars in Nuclear Medicine 2016, 46 (1) , 20-27. https://doi.org/10.1053/j.semnuclmed.2015.09.001
  100. Benjamin H. Rotstein, Michael S. Placzek, Hema S. Krishnan, Aleksandra Pekošak, Thomas Lee Collier, Changning Wang, Steven H. Liang, Ethan S. Burstein, Jacob M. Hooker, Neil Vasdev. Preclinical PET Neuroimaging of [ 11 C]Bexarotene. Molecular Imaging 2016, 15 , 153601211666305. https://doi.org/10.1177/1536012116663054
Load all citations
Download PDF

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Artistic representation of the radiotracer development process. Blue streams highlight one of many potential pathways for initial radiotracer development, which branches into two pathways after chemical design. Purple streams indicate radiotracer development pathways in which previously explored components are revisited for radiotracer optimization. Drawing used with permission of Aaron Keefe.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. Candidate biological targets for radiotracer development have diverse biochemical function and cellular localization. Established radiotracer targets include enzymes (red), receptors (blue), transporters (orange), and many other intracellular (green) and extracellular (purple) proteins.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. Three structurally related molecules with altered brain uptake and pharmacokinetics. (A) Chemical structure of the three molecules (1–3) that differ in the presence of methyl and phenyl groups; the ∗ indicates the 11C labeling site. (B) Transverse PET images for compounds 1–3 in baboon. (C) Time–activity curves for compounds 1–3. Adapted from ref 15.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. Impact of normalization of brain radiotracer signal to plasma radiotracer level. (A) Non-normalized baseline (blue) and self-blocked (yellow) brain signals for martinostat. (B) Integrated martinostat radioactivity in plasma during baseline (red) and self-blocked (gray) PET scans. (C) Plasma-normalized baseline (blue) and self-blocked (yellow) brain signals for martinostat. Adapted from ref 30.

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 53 other publications.

    1. 1
      Lockwood, A. H. Invasiveness in Studies of Brain Function by Positron Emission Tomography (PET) J. Cereb. Blood Flow Metab. 1985, 5, 487– 489
      1
      Invasiveness in studies of brain function by positron emission tomography (PET)
      Lockwood A H
      Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (1985), 5 (4), 487-9 ISSN:0271-678X.
      There is no expanded citation for this reference.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL28%252FjsVaitA%253D%253D&md5=0e851326d4c65e86b2d46adf77a46470
    2. 2
      Eriksson, L.; Kanno, I. Blood Sampling Devices and Measurements Med. Prog. Technol. 1991, 17, 249– 257
      2
      Blood sampling devices and measurements
      Eriksson L; Kanno I
      Medical progress through technology (1991), 17 (3-4), 249-57 ISSN:0047-6552.
      Quantitative positron emission tomography requires the determination of the tracer concentration in arterial plasma or full blood as a function of time. This defines the experimental input function. The model prediction, with which the positron camera regional time-activity curves are compared, is given by the experimental input function convoluted with the model. This paper reviews different strategies for determining the input function, invasive techniques, such as manual blood sampling and the use of automated blood sampling systems, and non-invasive techniques. The importance of corrections is discussed, such as accurate cross-calibrations of the different detectors used in quantitative PET and corrections for differences in time phase between the regional PET time-activity curves and the input function. We also report on the use of a PET system in non-invasive determinations of the input function. By imaging the neck region the time-activity curve of the carotid arteries can be obtained. The PET time-activity curves of the carotid arteries are in good agreement with a conventional experimental input function determined from the radial artery with an automated blood sampling system. However, PET time-activity curves of the radial arteries can not be used without a deconvolution since the resistance in the intact radial artery causes dispersion compared to the input function obtained by invasive methods.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK383lt1OlsQ%253D%253D&md5=38fa8d292c658c13a29dafcfcf245d33
    3. 3
      Zimmer, L.; Luxen, A. PET Radiotracers for Molecular Imaging in the Brain: Past, Present and Future NeuroImage 2012, 61, 363– 370
      There is no corresponding record for this reference.
    4. 4
      Hargreaves, R. J.; Rabiner, E. A. Translational PET Imaging Research Neurobiol. Dis. 2014, 61, 32– 38
      4
      Translational PET imaging research
      Hargreaves Richard J; Rabiner Eugenii A
      Neurobiology of disease (2014), 61 (), 32-8 ISSN:.
      The goal of any early central nervous system (CNS) drug development program is always to test the mechanism and not the molecule in order to support additional research investments in late phase clinical trials. Confirmation that drugs reach their targets using translational positron emission tomography (PET) imaging markers of engagement is central to successful clinical proof-of-concept testing and has become an important feature of most neuropsychiatric drug development programs. CNS PET imaging can also play an important role in the clinical investigation of the neuropharmacological basis of psychiatric disease and the optimization of drug therapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252FgtVGlsg%253D%253D&md5=84b76b18c4006d60f1b420ae0ebeb903
    5. 5
      CNS Radiotracer Table http://www.nimh.nih.gov/research-priorities/therapeutics/cns-radiotracer-table.shtml (accessed Jun 17, 2014) .
      There is no corresponding record for this reference.
    6. 6
      Martins-de-Souza, D.; Carvalho, P. C.; Schmitt, A.; Junqueira, M.; Nogueira, F. C. S.; Turck, C. W.; Domont, G. B. Deciphering the Human Brain Proteome: Characterization of the Anterior Temporal Lobe and Corpus Callosum as Part of the Chromosome 15-Centric Human Proteome Project J. Proteome Res. 2014, 13, 147– 157
      6
      Deciphering the Human Brain Proteome: Characterization of the Anterior Temporal Lobe and Corpus Callosum As Part of the Chromosome 15-centric Human Proteome Project
      Martins-de-Souza, Daniel; Carvalho, Paulo C.; Schmitt, Andrea; Junqueira, Magno; Nogueira, Fabio C. S.; Turck, Christoph W.; Domont, Gilberto B.
      Journal of Proteome Research (2014), 13 (1), 147-157CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      Defining the proteomes encoded by each chromosome and characterizing proteins related to human illnesses are among the goals of the Chromosome-centric Human Proteome Project (C-HPP) and the Biol. and Disease-driven HPP. Following these objectives, the authors studied the proteomes of the human anterior temporal lobe (ATL) and corpus callosum (CC) collected post-mortem from eight subjects. Using a label-free GeLC-MS/MS approach, the authors identified 2454 proteins in the ATL and 1887 in the CC through roughly 7500 and 5500 peptides, resp. Considering that the ATL is a gray-matter region while the CC is a white-matter region, they presented proteomes specific to their functions. Besides, 38 proteins are differentially expressed between the two regions. Furthermore, the proteome data sets were classified according to their chromosomal origin, and five proteins were evidenced at the MS level for the first time. The authors identified 70 proteins of the chromosome 15 - one of them for the first time by MS - which were submitted to an in silico pathway anal. These revealed branch point proteins assocd. with Prader-Willi and Angelman syndromes and dyskeratosis congenita, which are chromosome-15-assocd. diseases. Data presented here can be a useful for brain disorder studies as well as for contributing to the C-HPP initiative. The authors' data are publicly available as resource data to C-HPP participant groups at http://yoda.iq.ufrj.br/Daniel/chpp2013. Addnl., the mass spectrometry proteomics data have been deposited to the ProteomeXchange with identifier PXD000547 for the corpus callosum and PXD000548 for the anterior temporal lobe.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVCisL%252FE&md5=af81b7085d9ae5bb39e55342517a00f8
    7. 7
      Jones, T.; Rabiner, E. A. PET Research Advisory Company. The Development, Past Achievements, and Future Directions of Brain PET J. Cereb. Blood Flow Metab. 2012, 32, 1426– 1454
      7
      The development, past achievements, and future directions of brain PET
      Jones, Terry; Rabiner, Eugenii A.
      Journal of Cerebral Blood Flow & Metabolism (2012), 32 (7), 1426-1454CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)
      A review. The early developments of brain positron emission tomog. (PET), including the methodol. advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clin. applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodol. and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochem. technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments. Journal of Cerebral Blood Flow & Metab. (2012) 32, 1426-1454; doi:10.1038/jcbfm.2012.20; published online 21 March 2012.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVSjtr8%253D&md5=4175eb96622d701f626088265b81265a
    8. 8
      Ho, N. F.; Hooker, J. M.; Sahay, A.; Holt, D. J.; Roffman, J. L. In Vivo Imaging of Adult Human Hippocampal Neurogenesis: Progress, Pitfalls and Promise Mol. Psychiatry 2013, 18, 404– 416
      8
      In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise
      Ho N F; Hooker J M; Sahay A; Holt D J; Roffman J L
      Molecular psychiatry (2013), 18 (4), 404-16 ISSN:.
      New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult-born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot establish its functional importance in human health, disease and new treatment development. Current non-invasive neuroimaging modalities can provide live snapshots of the brain's structure, chemistry, activity and connectivity. This review explores whether existing macroscopic imaging methods can be used to understand the microscopic dynamics of adult hippocampal neurogenesis in living individuals. We discuss recent studies that have found correlations between neuroimaging measures of human hippocampal biology and levels of pro- or anti-neurogenic stimuli, weigh whether these correlations reflect changes in adult neurogenesis, detail the conceptual and technical limitations of these studies and elaborate on what will be needed to validate in vivo neuroimaging measures of adult neurogenesis for future investigations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svhtFGrtw%253D%253D&md5=6f5fe4614c5f101b2ff65054cf7edae8
    9. 9
      Wang, C.; Schroeder, F. A.; Hooker, J. M. Visualizing Epigenetics: Current Advances and Advantages in HDAC PET Imaging Techniques Neuroscience 2014, 264, 186– 197
      There is no corresponding record for this reference.
    10. 10
      Schroeder, F. A.; Wang, C.; Van de Bittner, G.; Neelamegam, R.; Takakura, W.; Karunakaran, P.; Wey, H.-Y.; Reis, S.; Gale, J. P.; Zhang, Y.-L.; Holson, E.; Haggarty, S.; Hooker, J. PET Imaging Demonstrates Histone Deacetylase Target Engagement and Clarifies Brain Penetrance of Known and Novel Small Molecule Inhibitors in Rat ACS Chem. Neurosci. 2014,  DOI: 10.1021/cn500162j
      There is no corresponding record for this reference.
    11. 11
      Biegon, A.; Kim, S. W.; Alexoff, D. L.; Jayne, M.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J. S. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies with PET and [N-Methyl-11C]vorozole Synapse 2010, 64, 801– 807
      There is no corresponding record for this reference.
    12. 12
      Kim, S. W.; Hooker, J. M.; Otto, N.; Win, K.; Muench, L.; Shea, C.; Carter, P.; King, P.; Reid, A. E.; Volkow, N. D.; Fowler, J. S. Whole-Body Pharmacokinetics of HDAC Inhibitor Drugs, Butyric Acid, Valproic Acid and 4-Phenylbutyric Acid Measured with Carbon-11 Labeled Analogs by PET Nucl. Med. Biol. 2013, 40, 912– 918
      12
      Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET
      Kim, Sung Won; Hooker, Jacob M.; Otto, Nicola; Win, Khaing; Muench, Lisa; Shea, Colleen; Carter, Pauline; King, Payton; Reid, Alicia E.; Volkow, Nora D.; Fowler, Joanna S.
      Nuclear Medicine and Biology (2013), 40 (7), 912-918CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
      The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to det. the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogs and performed dynamic positron emission tomog. (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepd. by using 11CO2 and the appropriate Grignard reagents. [11C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compd. at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compd. at 30 min after their administration resp. The brain uptake of all three carboxylic acids was very low (< 0.006%ID/cc, BA > VPA > PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [11C]BA showed relatively high uptake in spleen and pancreas whereas [11C]PBA showed high uptake in liver and heart. Notably, [11C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metab. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFynt77P&md5=fdc05c5c4822dfff4ffa9e7eee8f80dc
    13. 13
      Seo, Y. J.; Muench, L.; Reid, A.; Chen, J.; Kang, Y.; Hooker, J. M.; Volkow, N. D.; Fowler, J. S.; Kim, S. W. Radionuclide Labeling and Evaluation of Candidate Radioligands for PET Imaging of Histone Deacetylase in the Brain Bioorg. Med. Chem. Lett. 2013, 23, 6700– 6705
      There is no corresponding record for this reference.
    14. 14
      Wang, C.; Eessalu, T. E.; Barth, V. N.; Mitch, C. H.; Wagner, F. F.; Hong, Y.; Neelamegam, R.; Schroeder, F. A.; Holson, E. B.; Haggarty, S. J.; Hooker, J. M. Design, Synthesis, and Evaluation of Hydroxamic Acid-Based Molecular Probes for in Vivo Imaging of Histone Deacetylase (HDAC) in Brain Am. J. Nucl. Med. Mol. Imaging 2013, 4, 29– 38
      14
      Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain
      Wang Changning; Neelamegam Ramesh; Hooker Jacob M; Eessalu Thomas E; Barth Vanessa N; Mitch Charles H; Wagner Florence F; Holson Edward B; Hong Yijia; Schroeder Frederick A; Haggarty Stephen J
      American journal of nuclear medicine and molecular imaging (2013), 4 (1), 29-38 ISSN:2160-8407.
      Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czhtFersw%253D%253D&md5=2838a5695f30ae031ca6f97d26dc7250
    15. 15
      Seo, Y. J.; Kang, Y.; Muench, L.; Reid, A.; Caesar, S.; Jean, L.; Wagner, F.; Holson, E.; Haggarty, S. J.; Weiss, P.; King, P.; Carter, P.; Volkow, N. D.; Fowler, J. S.; Hooker, J. M.; Kim, S. W. Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors ACS Chem. Neurosci. 2014, 5, 588– 596
      15
      Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors
      Seo, Young Jun; Kang, Yeona; Muench, Lisa; Reid, Alicia; Caesar, Shannon; Jean, Logan; Wagner, Florence; Holson, Edward; Haggarty, Stephen J.; Weiss, Philipp; King, Payton; Carter, Pauline; Volkow, Nora D.; Fowler, Joanna S.; Hooker, Jacob M.; Kim, Sung Won
      ACS Chemical Neuroscience (2014), 5 (7), 588-596CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addn. to low HDAC potency and selectivity obsd., poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here the authors report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compds. based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compd. to feed back into the design process. A total of 17 compds. were evaluated, revealing mols. with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivs. exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivs. showed high BBB penetration (∼0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate mols. for small mol. probes and drugs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmvF2msb4%253D&md5=c59102403f07049034e1cd0a47161eb6
    16. 16
      Nordberg, A. PET Tracers for Beta-Amyloid and Other Proteinopathies. In PET and SPECT of Neurobiological Systems; Dierckx, R. A. J. O.; Otte, A.; de Vries, E. F. J.; van Waarde, A.; Luiten, P. G. M., Eds.; Springer: Berlin Heidelberg, 2014; pp 199– 212.
      There is no corresponding record for this reference.
    17. 17
      Zhang, L.; Villalobos, A.; Beck, E. M.; Bocan, T.; Chappie, T. A.; Chen, L.; Grimwood, S.; Heck, S. D.; Helal, C. J.; Hou, X.; Humphrey, J. M.; Lu, J.; Skaddan, M. B.; McCarthy, T. J.; Verhoest, P. R.; Wager, T. T.; Zasadny, K. Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand J. Med. Chem. 2013, 56, 4568– 4579
      17
      Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand
      Zhang, Lei; Villalobos, Anabella; Beck, Elizabeth M.; Bocan, Thomas; Chappie, Thomas A.; Chen, Laigao; Grimwood, Sarah; Heck, Steven D.; Helal, Christopher J.; Hou, Xinjun; Humphrey, John M.; Lu, Jiemin; Skaddan, Marc B.; McCarthy, Timothy J.; Verhoest, Patrick R.; Wager, Travis T.; Zasadny, Kenneth
      Journal of Medicinal Chemistry (2013), 56 (11), 4568-4579CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      To accelerate the discovery of novel small mol. central nervous system (CNS) positron emission tomog. (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET ligands that have successfully reached the clinic and 15 radioligands that failed in late-stage development as neg. controls. A systematic anal. of these ligands identified a set of preferred parameters for physicochem. properties, brain permeability, and nonspecific binding (NSB). These preferred parameters have subsequently been applied to several programs and have led to the successful development of novel PET ligands with reduced resources and timelines. This strategy is illustrated here by the discovery of the novel phosphodiesterase 2A (PDE2A) PET ligand 4-(3-[18F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine, [18F]PF-05270430 (5).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntFyhtro%253D&md5=ee7ce04829d7456a632c02c331c4edfa
    18. 18
      Ferré, S.; Casadó, V.; Devi, L. A.; Filizola, M.; Jockers, R.; Lohse, M. J.; Milligan, G.; Pin, J.-P.; Guitart, X. G Protein-Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives Pharmacol. Rev. 2014, 66, 413– 434
      There is no corresponding record for this reference.
    19. 19
      Sander, C. Y.; Hooker, J. M.; Catana, C.; Normandin, M. D.; Alpert, N. M.; Knudsen, G. M.; Vanduffel, W.; Rosen, B. R.; Mandeville, J. B. Neurovascular Coupling to D2/D3 Dopamine Receptor Occupancy Using Simultaneous PET/functional MRI Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 11169– 11174
      There is no corresponding record for this reference.
    20. 20
      Patel, S.; Gibson, R. In Vivo Site-Directed Radiotracers: A Mini-Review Nucl. Med. Biol. 2008, 35, 805– 815
      20
      In vivo site-directed radiotracers: a mini-review
      Patel, Shil; Gibson, Raymond
      Nuclear Medicine and Biology (2008), 35 (8), 805-815CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)
      A review on the process for developing reversible, monovalent site-specific radiotracers in drug design. It is concerned with the characteristics of radiotracers such as binding, lipophilicity, and binding specificity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVaisLvL&md5=869985e0741d52a76cb546972097e2a8
    21. 21
      Wang, Y.; Zhang, Y.-L.; Hennig, K.; Gale, J. P.; Hong, Y.; Cha, A.; Riley, M.; Wagner, F.; Haggarty, S. J.; Holson, E.; Hooker, J. Class I HDAC Imaging Using [(3)H]CI-994 Autoradiography Epigenetics 2013, 8, 756– 764
      There is no corresponding record for this reference.
    22. 22
      Gage, H. D.; Voytko, M. L.; Ehrenkaufer, R. L.; Tobin, J. R.; Efange, S. M.; Mach, R. H. Reproducibility of Repeated Measures of Cholinergic Terminal Density Using [18F](+)-4-Fluorobenzyltrozamicol and PET in the Rhesus Monkey Brain J. Nucl. Med. 2000, 41, 2069– 2076
      There is no corresponding record for this reference.
    23. 23
      Narendran, R.; Mason, N. S.; May, M. A.; Chen, C.-M.; Kendro, S.; Ridler, K.; Rabiner, E. A.; Laruelle, M.; Mathis, C. A.; Frankle, W. G. Positron Emission Tomography Imaging of Dopamine D2/3 Receptors in the Human Cortex with [11C]FLB 457: Reproducibility Studies Synapse 2011, 65, 35– 40
      There is no corresponding record for this reference.
    24. 24
      Wahl, L. M.; Nahmias, C. Statistical Power Analysis for PET Studies in Humans J. Nucl. Med. 1998, 39, 1826– 1829
      There is no corresponding record for this reference.
    25. 25
      Stephenson, K. A.; van Oosten, E. M.; Wilson, A. A.; Meyer, J. H.; Houle, S.; Vasdev, N. Synthesis and Preliminary Evaluation of [(18)F]-Fluoro-(2S)-Exaprolol for Imaging Cerebral Beta-Adrenergic Receptors with PET Neurochem. Int. 2008, 53, 173– 179
      25
      Synthesis and preliminary evaluation of [18F]-fluoro-(2S)-Exaprolol for imaging cerebral β-adrenergic receptors with PET
      Stephenson, Karin A.; van Oosten, Erik M.; Wilson, Alan A.; Meyer, Jeffrey H.; Houle, Sylvain; Vasdev, Neil
      Neurochemistry International (2008), 53 (5), 173-179CODEN: NEUIDS; ISSN:0197-0186. (Elsevier B.V.)
      Cerebral β-adrenergic receptors (β-ARs) are of interest in several disorders including Parkinson's disease, Alzheimer's disease and in particular major depressive disorder. Development of a positron emission tomog. (PET) ligand for imaging β-ARs would allow the quantification of these receptors in the living human brain so as to better understand both the pathophysiol. of depression and how to improve treatment. Currently there are no radioligands suitable for this purpose. In an attempt to achieve this goal, we prepd. [18F]-labeled (2S)-1-(1-fluoropropan-2-ylamino)-3-(2-cyclohexylphenoxy)propan-2-ol (fluoro-Exaprolol; (2 S )-1). Radiolabeling with fluorine-18 was accomplished via prepn. of a precursor contg. a tosyl leaving group (10), and utilizes the 2-oxazolidinone group to simultaneously protect both the amine and hydroxy groups. The oxazolidinone was readily removed with lithium aluminum hydride following a nucleophilic [18F]-fluoride for tosyl displacement to prep. [18 F]-(2 S)-1 in 31% radiochem. yield (uncorrected for decay), with >98% radiochem. purity in <1 h. The specific activity of the formulated product was 927 mCi/μmol and the log P (pH 7.4) was 2.97. Preliminary biol. evaluations in conscious rats indicated that [18 F]-(2 S)-1 had good brain uptake for imaging (0.8-1.3% injected dose/g (% ID/g) of wet tissue, 5 min post-injection of the radiotracer) with a slow washout (>0.5% ID/g at 60 min post-injection) in all brain regions. Pharmacol. challenges indicate that the binding is largely non-specific, as administration of Propranolol, authentic (2 S)-1, or WAY 100635 prior to injection of [18 F]-(2 S)-1 did not block uptake of the radiotracer. These results indicate that [18 F]-(2 S)-1 is not a suitable candidate for PET imaging of cerebral β-ARs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFOltbjJ&md5=0832cfa393ee025f12dc4624737670c8
    26. 26
      Wang, C.; Wilson, C. M.; Moseley, C. K.; Carlin, S. M.; Hsu, S.; Arabasz, G.; Schroeder, F. A.; Sander, C. Y.; Hooker, J. M. Evaluation of Potential PET Imaging Probes for the Orexin 2 Receptors Nucl. Med. Biol. 2013, 40, 1000– 1005
      26
      Evaluation of potential PET imaging probes for the orexin 2 receptors
      Wang, Changning; Wilson, Colin M.; Moseley, Christian K.; Carlin, Stephen M.; Hsu, Shirley; Arabasz, Grae; Schroeder, Frederick A.; Sander, Christin Y.; Hooker, Jacob M.
      Nuclear Medicine and Biology (2013), 40 (8), 1000-1005CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
      A wide range of central nervous system (CNS) disorders, particularly those related to sleep, are assocd. with the abnormal function of orexin (OX) receptors. Several orexin receptor antagonists have been reported in recent years, but currently there are no imaging tools to probe the d. and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomog. (PET) radiotracer development could be used to elucidate the assocn. of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compds. based on diazepane orexin receptor antagonists previously described. One of the synthesized compds., [11C]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR imaging. PET scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [11C]CW4 exhibited fast kinetics and high nonspecific binding, as detd. after co-administration of [11C]CW4 and unlabeled CW4. These properties indicate that [11C]CW4 has excellent brain penetrance and could be used as a lead compd. for developing new CNS-penetrant PET imaging probes of orexin receptors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yhsrvK&md5=3219170035ebadd30300dd139ceb3883
    27. 27
      Neelamegam, R.; Hellenbrand, T.; Schroeder, F. A.; Wang, C.; Hooker, J. M. Imaging Evaluation of 5HT2C Agonists, [(11)C]WAY-163909 and [(11)C]Vabicaserin, Formed by Pictet-Spengler Cyclization J. Med. Chem. 2014, 57, 1488– 1494
      There is no corresponding record for this reference.
    28. 28
      Horti, A. G.; Gao, Y.; Kuwabara, H.; Dannals, R. F. Development of Radioligands with Optimized Imaging Properties for Quantification of Nicotinic Acetylcholine Receptors by Positron Emission Tomography Life Sci. 2010, 86, 575– 584
      There is no corresponding record for this reference.
    29. 29
      Pike, V. W. PET Radiotracers: Crossing the Blood-Brain Barrier and Surviving Metabolism Trends Pharmacol. Sci. 2009, 30, 431– 440
      29
      PET radiotracers: crossing the blood-brain barrier and surviving metabolism
      Pike, Victor W.
      Trends in Pharmacological Sciences (2009), 30 (8), 431-440CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)
      A review. Radiotracers for imaging protein targets in the living human brain with positron emission tomog. (PET) are increasingly useful in clin. research and in drug development. Such radiotracers must fulfill many criteria, among which an ability to enter brain adequately and reversibly without contamination by troublesome radiometabolites is desirable for accurate measurement of the d. of a target protein (e.g. neuroreceptor, transporter, enzyme or plaque). Candidate radiotracers can fail as a result of poor passive brain entry, rejection from brain by efflux transporters or undesirable metab. These issues are reviewed. Emerging PET radiotracers for measuring efflux transporter function and new strategies for ameliorating radiotracer metab. are discussed. A growing understanding of the mol. features affecting the brain penetration, metab. and efflux transporter sensitivity of prospective radiotracers should ultimately lead to their more rational and efficient design, and also to their greater efficacy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpt1KgsLg%253D&md5=97704995fecd968baf1e0892bf70324e
    30. 30
      Wang, C.; Schroeder, F. A.; Wey, H.-Y.; Borra, R.; Wagner, F.; Reis, S.; Kim, S. W.; Holson, E. B.; Haggarty, S. J.; Hooker, J. M. In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs J. Med. Chem. 2014,  DOI: 10.1021/jm500872p
      There is no corresponding record for this reference.
    31. 31
      Hooker, J. M. Modular Strategies for PET Imaging Agents Curr. Opin. Chem. Biol. 2010, 14, 105– 111
      31
      Modular strategies for PET imaging agents
      Hooker, Jacob M.
      Current Opinion in Chemical Biology (2010), 14 (1), 105-111CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      A review. In recent years, modular and simplified chem. and biol. strategies have been developed for the synthesis and implementation of positron emission tomog. (PET) radiotracers. New developments in bioconjugation and synthetic methodologies, in combination with advances in macromol. delivery systems and gene-expression imaging, reflect a need to reduce radiosynthesis burden in order to accelerate imaging agent development. These new approaches, which are often mindful of existing infrastructure and available resources, are anticipated to provide a more approachable entry point for researchers interested in using PET to translate in vitro research to in vivo imaging.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht12qt7w%253D&md5=2933036c778dcd76b3cdf2afc4067909
    32. 32
      Sutcliffe-Goulden, J. L.; O’Doherty, M. J.; Marsden, P. K.; Hart, I. R.; Marshall, J. F.; Bansal, S. S. Rapid Solid Phase Synthesis and Biodistribution of 18F-Labelled Linear Peptides Eur. J. Nucl. Med. Mol. Imaging 2002, 29, 754– 759
      32
      Rapid solid phase synthesis and biodistribution of 18F-labeled linear peptides
      Sutcliffe-Goulden, Julie L.; O'Doherty, Michael J.; Marsden, Paul K.; Hart, Ian R.; Marshall, John F.; Bansal, Sukvinder S.
      European Journal of Nuclear Medicine and Molecular Imaging (2002), 29 (6), 754-759CODEN: EJNMA6; ISSN:1619-7070. (Springer-Verlag)
      A rapid method for radiolabeling short peptides with 18F (t1/2=109.7 min) for use in positron emission tomog. (PET) was developed. Linear peptides (13-mers) were synthesized using solid phase peptide synthesis and 9-fluorenylmethoxycarbonyl (Fmoc) chem. The peptides were assembled on a solid-phase polyethylene glycol-polystyrene support using the "hyper acid labile" linker xanthen-2-oxyvaleric acid and were labeled in situ with 4-[19F]- or 4-[18F]fluorobenzoic acid. Optimum coupling of 4-[19F]fluorobenzoic acid to the peptidyl resin was achieved within 2 min using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU/DIPEA), and optimum cleavage was achieved within 7 min using trifluoroacetic acid/phenol/water/Triisopropylsilane at 37°C. The linear peptides were rapidly labeled with 4-[18F]fluorobenzoic acid with an overall radiochem. yield of 80%-90% (decay cor.), a radiochem. purity of >95% without HPLC purifn. and an overall synthesis time of 20 min. This novel method was used to label peptides contg. the arginine-glycine-aspartic acid (RGD) motif, the binding site of many integrins. In vitro studies showed that the fluorobenzoyl prosthetic group had no deleterious effect on the ability of these peptides to inhibit the binding of human cells via integrins. Biodistribution studies in tumor-bearing mice showed that although the linear peptides were rapidly removed from the circulation by the liver and kidneys, there was a transient and non-RGD-dependent accumulation in the tumor of both the test and the control peptides. The use of more selective peptides with a longer half-life in the circulation combined with this rapid labeling technique will significantly enhance the application of peptides in PET.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvVWnu7s%253D&md5=b7cf5a3b76bb3fdcf48e8a0fd2ad18e6
    33. 33
      Gagnon, M. K. J.; Hausner, S. H.; Marik, J.; Abbey, C. K.; Marshall, J. F.; Sutcliffe, J. L. High-Throughput in Vivo Screening of Targeted Molecular Imaging Agents Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 17904– 17909
      There is no corresponding record for this reference.
    34. 34
      Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Synthesis of 11C, 18F, 15O, and 13N Radiolabels for Positron Emission Tomography Angew. Chem., Int. Ed. 2008, 47, 8998– 9033
      There is no corresponding record for this reference.
    35. 35
      Cole, E. L.; Stewart, M. N.; Littich, R.; Hoareau, R.; Scott, P. J. H. Radiosyntheses Using Fluorine-18: The Art and Science of Late Stage Fluorination Curr. Top. Med. Chem. 2014, 14, 875– 900
      35
      Radiosyntheses using Fluorine-18: The Art and Science of Late Stage Fluorination
      Cole, Erin L.; Stewart, Megan N.; Littich, Ryan; Hoareau, Raphael; Scott, Peter J. H.
      Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (7), 875-900CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
      A review. Positron (β+) emission tomog. (PET) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiol. structures and biochem. pathways. The continued growth of PET imaging relies on a corresponding increase in access to radiopharmaceuticals (biol. active mols. labeled with short-lived radionuclides such as fluorine-18). This unique need to incorporate the short-lived fluorine-18 atom (t1/2 = 109.77 min) as late in the synthetic pathway as possible has made development of methodologies that enable rapid and efficient late stage fluorination an area of research within its own right. In this review we describe strategies for radiolabeling with fluorine-18, including classical fluorine-18 radiochem. and emerging techniques for late stage fluorination reactions, as well as labeling technologies such as microfluidics and solid-phase radiochem. The utility of fluorine-18 labeled radiopharmaceuticals is showcased through recent applications of PET imaging in the healthcare, personalized medicine and drug discovery settings.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlt1SgtbY%253D&md5=25ced9ea824e1c9e6dd55bc91bda4fdd
    36. 36
      Zhang, M.-R.; Suzuki, K. [18F]Fluoroalkyl Agents: Synthesis, Reactivity and Application for Development of PET Ligands in Molecular Imaging Curr. Top. Med. Chem. 2007, 7, 1817– 1828
      36
      [18F]fluoroalkyl agents: synthesis, reactivity and application for development of PET ligands in molecular imaging
      Zhang, Ming-Rong; Suzuki, Kazutoshi
      Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2007), 7 (18), 1817-1828CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
      A review. Fluorine-18 (18F, β+; 96.7%, T1/2 = 109.8 min) is of considerable importance for developing positron emission tomog. (PET) ligands for imaging receptor, enzyme, gene expression etc. in brain, tumor, myocardium and other regions or organs due to its optimal decay characteristics. To synthesize 18F-labeled PET ligands, reliable labeling techniques inserting 18F into a target mol. are necessary. [18F]Fluoroalkylation is a useful way of introducing 18F into target mols. contg. amino, phenol, thiophenol, and amide functional groups. Here, the authors review the prepn., reactivity and application of [18F]fluoroalkyl agents for the development of 18F-labeled PET ligands in mol. imaging. [18F]Fluoroalkyl agents have been synthesized by reacting [18F]F- with the corresponding alkyl derivs. contg. halogen and sulfonate as leaving groups. After the fluorination reaction, the radiolabeled products with relatively low b.ps. were distd. from the reaction mixts., sometimes added by Sep-Pak or gas chromatog. sepn. The [18F]fluoromethyl compds. have high reactivity with nucleophilic substrates, but many [18F]fluoromethylated compds. are in vitro unstable. To increase the efficiency of [18F]fluoroethylation, [18F]FCH2CH2Br, the most frequently used [18F]fluoroethyl agent, was converted into [18F]FCH2CH2I or [18F]FCH2CH2OTf in situ. Most [18F]fluoromethylated ligands were found to be in vivo unstable due to defluorination. Deuterium substitution for the fluoromethyl group reduced defluorination to an extent. A no. of [18F]fluoroethylated PET ligands have been developed for animal evaluation and clin. investigation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVOrtb3F&md5=9a962abf194338e920477c5ca32703f0
    37. 37
      Pretze, M.; Pietzsch, D.; Mamat, C. Recent Trends in Bioorthogonal Click-Radiolabeling Reactions Using Fluorine-18 Molecules 2013, 18, 8618– 8665
      37
      Recent trends in bioorthogonal click-radiolabeling reactions using fluorine-18
      Pretze, Marc; Pietzsch, Doreen; Mamat, Constantin
      Molecules (2013), 18 (), 8618-8665CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      A review. The increasing application of positron emission tomog. (PET) in nuclear medicine has stimulated the extensive development of a multitude of novel and versatile bioorthogonal conjugation techniques esp. for the radiolabeling of biol. active high mol. wt. compds. like peptides, proteins or antibodies. Taking into consideration that the introduction of fluorine-18 (t1/2 = 109.8 min) proceeds under harsh conditions, radiolabeling of these biol. active mols. represents an outstanding challenge and is of enormous interest. Special attention has to be paid to the method of 18F-introduction. It should proceed in a regioselective manner under mild physiol. conditions, in an acceptable time span, with high yields and high specific activities. For these reasons and due to the high no. of functional groups found in these compds., a specific labeling procedure has to be developed for every bioactive macromol. Bioorthogonal strategies including the Cu-assisted Huisgen cycloaddn. and its copper-free click variant, both Staudinger Ligations or the tetrazine-click reaction have been successfully applied and represent valuable alternatives for the selective introduction of fluorine-18 to overcome the afore mentioned obstacles. This comprehensive review deals with the progress and illustrates the latest developments in the field of bioorthogonal labeling with the focus on the prepn. of radiofluorinated building blocks and tracers for mol. imaging.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ert7nI&md5=2c162751f76f760e57080404678e3d8b
    38. 38
      Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T. A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging Science 2011, 334, 639– 642
      38
      A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging
      Lee, Eunsung; Kamlet, Adam S.; Powers, David C.; Neumann, Constanze N.; Boursalian, Gregory B.; Furuya, Takeru; Choi, Daniel C.; Hooker, Jacob M.; Ritter, Tobias
      Science (Washington, DC, United States) (2011), 334 (6056), 639-642CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      The unnatural isotope fluorine-18 (18F) is used as a positron emitter in mol. imaging. Currently, many potentially useful 18F-labeled probe mols. are inaccessible for imaging because no fluorination chem. is available to make them. The 110-min half-life of 18F requires rapid syntheses for which [18F]fluoride is the preferred source of fluorine because of its practical access and suitable isotope enrichment. However, conventional [18F]fluoride chem. has been limited to nucleophilic fluorination reactions. We report the development of a palladium-based electrophilic fluorination reagent derived from fluoride and its application to the synthesis of arom. 18F-labeled mols. via late-stage fluorination. Late-stage fluorination enables the synthesis of conventionally unavailable positron emission tomog. (PET) tracers for anticipated applications in pharmaceutical development as well as preclin. and clin. PET imaging.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyqu7vL&md5=ede2fa164d6ce80035e5482966b5b57e
    39. 39
      Lee, E.; Hooker, J. M.; Ritter, T. Nickel-Mediated Oxidative Fluorination for PET with Aqueous [18F] Fluoride J. Am. Chem. Soc. 2012, 134, 17456– 17458
      There is no corresponding record for this reference.
    40. 40
      Kamlet, A. S.; Neumann, C. N.; Lee, E.; Carlin, S. M.; Moseley, C. K.; Stephenson, N.; Hooker, J. M.; Ritter, T. Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation PLoS One 2013, 8e59187
      There is no corresponding record for this reference.
    41. 41
      Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.; Groves, J. T. Late Stage Benzylic C–H Fluorination with [18F]Fluoride for PET Imaging J. Am. Chem. Soc. 2014, 136, 6842– 6845
      There is no corresponding record for this reference.
    42. 42
      Ren, H.; Wey, H.-Y.; Strebl, M.; Neelamegam, R.; Ritter, T.; Hooker, J. M. Synthesis and Imaging Validation of [18F]MDL100907 Enabled by Ni-Mediated Fluorination ACS Chem. Neurosci. 2014, 5, 611– 615
      42
      Synthesis and Imaging Validation of [18F]MDL100907 Enabled by Ni-Mediated Fluorination
      Ren, Hong; Wey, Hsiao-Ying; Strebl, Martin; Neelamegam, Ramesh; Ritter, Tobias; Hooker, Jacob M.
      ACS Chemical Neuroscience (2014), 5 (7), 611-615CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Several voids exist in reliable positron emission tomog. (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clin. research. Herein we address an unmet need in 5HT2a imaging using innovative chem. We report a scalable and robust synthesis of [18F]MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [18F]fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [18F]MDL100907. Using the new synthetic strategy and optimized procedure, [18F]MDL100907 was evaluated against [11C]MDL100907 for reliability to quantify 5HT2a in the nonhuman primate brain and was found to be superior based on a single scan anal. using the same nonhuman primate. The use of this new 5HT2a radiotracer will afford clin. neuroscience research the ability to distinguish 5HT2a receptor abnormalities binding between healthy subjects and patients even when group differences are small.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXot1yiu7g%253D&md5=067d3790608ae9f0cbe0c8d14a727651
    43. 43
      Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings Adv. Drug Delivery Rev. 2001, 46, 3– 26
      43
      Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
      Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
      Advanced Drug Delivery Reviews (2001), 46 (1-3), 3-26CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)
      A review with 50 refs. Exptl. and computational approaches to est. soly. and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the mol. wt. (MWT) is greater than 500 and the calcd. Log P (CLogP) is greater than 5 (or MlogP >4.15). Computational methodol. for the rule-based Moriguchi Log P (MLogP) calcn. is described. Turbidimetric soly. measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric soly. than leads in the pre-HTS era. In the development setting, soly. calcns. focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with exptl. thermodn. soly. measurements.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXitVOhs7o%253D&md5=c60bb89da68f051c0ee7ac4c0468a0e4
    44. 44
      Ryu, Y. H.; Liow, J.-S.; Zoghbi, S.; Fujita, M.; Collins, J.; Tipre, D.; Sangare, J.; Hong, J.; Pike, V. W.; Innis, R. B. Disulfiram Inhibits Defluorination of (18)F-FCWAY, Reduces Bone Radioactivity, and Enhances Visualization of Radioligand Binding to Serotonin 5-HT1A Receptors in Human Brain J. Nucl. Med. 2007, 48, 1154– 1161
      There is no corresponding record for this reference.
    45. 45
      Laruelle, M.; Slifstein, M.; Huang, Y. Positron Emission Tomography: Imaging and Quantification of Neurotransporter Availability Methods 2002, 27, 287– 299
      45
      Positron emission tomography: imaging and quantification of neurotransporter availability
      Laruelle, Marc; Slifstein, Mark; Huang, Yiyun
      Methods (San Diego, CA, United States) (2002), 27 (3), 287-299CODEN: MTHDE9; ISSN:1046-2023. (Elsevier Science)
      A review. Over the last decade, a large no. of radiotracers have been developed to image and quantify transporter availability with positron emission tomog. (PET) or single-photon emission computed tomog. (SPECT). Radiotracers suitable to image dopamine transporters (DATs) and serotonin transporters (SERTs) have been the object of most efforts. Following a brief overview of DAT and SERT radiotracers that have been demonstrated to be suitable for quant. anal. in vivo, this article describes the principal methods that have been used for the anal. of these data. Kinetic modeling is the most direct implementation of the compartment models, but with some tracers accurate input function measurement and good compartment configuration identification can be difficult to obtain. Other methods were designed to overcome some particular vulnerability to error of classic kinetic modeling, but introduced new vulnerabilities in the process. Ref. region methods obviate the need for arterial plasma measurement, but are not as robust to violations of the underlying modeling assumptions as methods using the arterial input function. Graphical methods give ests. of distribution vols. without the requirement of compartment model specification, but provide a biased estimator in the presence of statistical noise. True equil. methods are quite robust, but their use is limited to expts. with tracers that are suitable for const. infusion. In conclusion, no universally "best" method is applicable to all neurotransporter imaging studies, and careful evaluation of model-based methods is required for each radiotracer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmtFWhs74%253D&md5=1ec923e982f1769d80fd74b68d7b05ed
    46. 46
      NIMH Psychoactive Drug Screening Program. http://pdsp.med.unc.edu/ (accessed Jun 17, 2014) .
      There is no corresponding record for this reference.
    47. 47
      Hooker, J. M.; Kim, S. W.; Reibel, A. T.; Alexoff, D.; Xu, Y.; Shea, C. Evaluation of [11C]Metergoline as a PET Radiotracer for 5HTR in Nonhuman Primates Bioorg. Med. Chem. 2010, 18, 7739– 7745
      There is no corresponding record for this reference.
    48. 48
      Patel, S.; Hamill, T.; Hostetler, E.; Burns, H. D.; Gibson, R. E. An in Vitro Assay for Predicting Successful Imaging Radiotracers Mol. Imaging Biol. 2003, 5, 65– 71
      48
      An in vitro assay for predicting successful imaging radiotracers
      Patel Shil; Hamill Terence; Hostetler Eric; Burns H Donald; Gibson Raymond E
      Molecular imaging and biology (2003), 5 (2), 65-71 ISSN:1536-1632.
      PURPOSE: To develop an in vitro binding assay able to predict whether a radiolabel is likely to be a useful clinical tracer for positron emission tomography (PET). PROCEDURES: Rodent and rhesus brain sections were incubated with radioligands, most of which are tritiated or iodinated versions of known clinical PET radiotracers, and assayed for binding to brain receptors for a 20-minute period using a no-wash protocol (n=>/=3). RESULTS: Radiolabeled flumazenil (RO-151788), WAY100635, N-methylscopolamine, N-methylspiperone, raclopride, citalopram, (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), paroxetine, and 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-flurobenzamido]ethyl]piperazine (MPPF) were assessed for binding to either rhesus caudate putamen, and/or frontal cortex, or rat whole brain sections. Specific binding for these compounds ranged from 0 to 94% by 20 minutes. Those with %-specific binding less than 10% have also been shown to not be effective as in vivo PET radiotracers. In addition, successful PET radiotracers incubated in tissue sections with target receptor either absent or present in low density behaved poorly in this assay, as expected, as did radiolabels previously shown to possess high non-specific binding. CONCLUSIONS: An in vitro binding assay using rodent and rhesus brain sections has been developed that, within the currently assayed radiotracers, is able to rapidly predict whether a radiolabeled compound is a useful clinical PET radiotracer. This method suggests significant potential for the rapid in vitro evaluation of potential in vivo PET radiotracers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3svktFGmsQ%253D%253D&md5=4fe5e7e7ebdd730cad9a149782f7b0eb
    49. 49
      Barth, V.; Need, A. Identifying Novel Radiotracers for PET Imaging of the Brain: Application of LC-MS/MS to Tracer Identification ACS Chem. Neurosci. 2014,  DOI: 10.1021/cn500072r
      There is no corresponding record for this reference.
    50. 50
      Tournier, N.; Saba, W.; Cisternino, S.; Peyronneau, M.-A.; Damont, A.; Goutal, S.; Dubois, A.; Dollé, F.; Scherrmann, J.-M.; Valette, H.; Kuhnast, B.; Bottlaender, M. Effects of Selected OATP And/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide AAPS J. 2013, 15, 1082– 1090
      There is no corresponding record for this reference.
    51. 51
      Syvänen, S.; Lindhe, Ö.; Palner, M.; Kornum, B. R.; Rahman, O.; Långström, B.; Knudsen, G. M.; Hammarlund-Udenaes, M. Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport Drug Metab. Dispos. 2009, 37, 635– 643
      There is no corresponding record for this reference.
    52. 52
      Varnäs, K.; Varrone, A.; Farde, L. Modeling of PET Data in CNS Drug Discovery and Development J. Pharmacokinet. Pharmacodyn. 2013, 40, 267– 279
      52
      Modeling of PET data in CNS drug discovery and development
      Varnas Katarina; Varrone Andrea; Farde Lars
      Journal of pharmacokinetics and pharmacodynamics (2013), 40 (3), 267-79 ISSN:.
      Positron emission tomography (PET) is increasingly used in drug discovery and development for evaluation of CNS drug disposition and for studies of disease biomarkers to monitor drug effects on brain pathology. The quantitative analysis of PET data is based on kinetic modeling of radioactivity concentrations in plasma and brain tissue compartments. A number of quantitative methods of analysis have been developed that allow the determination of parameters describing drug pharmacokinetics and interaction with target binding sites in the brain. The optimal method of quantification depends on the properties of the radiolabeled drug or radioligand and the binding site studied. We here review the most frequently used methods for quantification of PET data in relation to CNS drug discovery and development. The utility of PET kinetic modeling in the development of novel CNS drugs is illustrated by examples from studies of the brain kinetic properties of radiolabeled drug molecules.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3snisVajtQ%253D%253D&md5=8afb967eb7584f68ed62fa08f7907a74
    53. 53
      Kuntner, C. Kinetic Modeling in Preclinical Positron Emission Tomography Z. Med. Phys. 2014,  DOI: 10.1016/j.zemedi.2014.02.003
      There is no corresponding record for this reference.
PDF [ 2MB]

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect