Characteristic Evaluation of a 11C-Labeled Leucine Analog, l-α-[5-11C]methylleucine, as a Tracer for Brain Tumor Imaging by Positron Emission Tomography
- Tsuyoshi Tahara*
Tsuyoshi Tahara*Email: [email protected]. Tel/Fax: +81-88-633-7749.RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanDepartment of In Vivo Imaging, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima 770-8503, JapanMore by Tsuyoshi Tahara
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- Shuhei Takatani
Shuhei TakataniRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Shuhei Takatani
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- Mieko Tsuji
Mieko TsujiRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Mieko Tsuji
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- Nina Shibata
Nina ShibataRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Nina Shibata
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- Nami Hosaka
Nami HosakaRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Nami Hosaka
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- Michiko Inoue
Michiko InoueRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Michiko Inoue
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- Masahiro Ohno
Masahiro OhnoRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Masahiro Ohno
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- Daiki Ozaki
Daiki OzakiRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Daiki Ozaki
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- Aya Mawatari
Aya MawatariRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Aya Mawatari
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- Yasuyoshi Watanabe
Yasuyoshi WatanabeRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Yasuyoshi Watanabe
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- Hisashi Doi
Hisashi DoiRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanMore by Hisashi Doi
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- Hirotaka Onoe
Hirotaka OnoeRIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanRIKEN Center for Life Science Technologies, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, JapanHuman Brain Research Center, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-Cho, Sakyo-ku, Kyoto 606-8507, JapanMore by Hirotaka Onoe
Abstract
Amino acid transporters are upregulated in many cancer cells, and system L amino acid transporters (LAT1–4), in particular, LAT1, which preferentially transports large, neutral, and branched side-chain amino acids, are considered a primary target for cancer positron emission tomography (PET) tracer development. Recently, we developed a 11C-labeled leucine analog, l-α-[5-11C]methylleucine ([5-11C]MeLeu), via a continuous two-step reaction of Pd0-mediated 11C-methylation and microfluidic hydrogenation. In this study, we evaluated the characteristics of [5-11C]MeLeu and also compared the sensitivity to brain tumors and inflammation with l-[11C]methionine ([11C]Met) to determine its potential for brain tumor imaging. Competitive inhibition experiments, protein incorporation, and cytotoxicity experiments of [5-11C]MeLeu were performed in vitro. Further, metabolic analyses of [5-11C]MeLeu were performed using a thin-layer chromatogram. The accumulation of [5-11C]MeLeu in tumor and inflamed regions of the brain was compared with [11C]Met and 11C-labeled (S)-ketoprofen methyl ester by PET imaging, respectively. Transporter assay with various inhibitors revealed that [5-11C]MeLeu is mainly transported via system L amino acid transporters, especially LAT1, into A431 cells. The protein incorporation assay and metabolic assay in vivo demonstrated that [5-11C]MeLeu was neither used for protein synthesis nor metabolized. These results indicate that MeLeu is very stable in vivo. Furthermore, the treatment of A431 cells with various concentrations of MeLeu did not change their viability, even at high concentrations (∼10 mM). In brain tumors, the tumor-to-normal ratio of [5-11C]MeLeu was more elevated than that of [11C]Met. However, the accumulation levels of [5-11C]MeLeu were lower than those of [11C]Met (the standardized uptake value (SUV) of [5-11C]MeLeu and [11C]Met was 0.48 ± 0.08 and 0.63 ± 0.06, respectively). In brain inflammation, no significant accumulation of [5-11C]MeLeu was observed at the inflamed brain area. These data suggested that [5-11C]MeLeu was identified as a stable and safe agent for PET tracers and could help detect brain tumors, which overexpress the LAT1 transporter.
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