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Radiosynthesis and evaluation of a negative allosteric modulator for the PET imaging of metabotropic glutamate receptor 2 in rat brain
https://repo.qst.go.jp/records/76128
https://repo.qst.go.jp/records/76128301116ed-82ba-46f1-955b-1bcbfdc503b7
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2019-06-03 | |||||
| タイトル | ||||||
| タイトル | Radiosynthesis and evaluation of a negative allosteric modulator for the PET imaging of metabotropic glutamate receptor 2 in rat brain | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Kumata, Katsushi
× Kumata, Katsushi× Zhang, Yiding× Hatori, Akiko× Yamasaki, Tomoteru× Kurihara, Yusuke× Nengaki, Nobuki× Ming-Rong, Zhang× Kumata, Katsushi× Zhang, Yiding× Hatori, Akiko× Yamasaki, Tomoteru× Kurihara, Yusuke× Nengaki, Nobuki× Ming-Rong, Zhang |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives Metabotropic glutamate receptor 2 (mGluR2) is related to a wide variety of brain functions. For this reason, mGluR2 has been appointed as a potential therapeutic target for several neuropsychiatric disorders such as anxiety, schizophrenia, and addiction. So far, several PET tracers targeting mGluR2 have been developed, some of which underwent preclinical imaging in animal studies, but no reliable radiotracer was used for clinical imaging of mGluR2 in human brain. In this study, we aimed to develop a new useful radiotracer for the visualization of mGluR2 in the brain. We established 4‐(2‐fluoro‐4‐methoxyphenyl)‐5‐((2‐methylpyridin‐4‐yl)methoxy)picolinamide (1) as a candidate for mGluR2. Compound 1, an analog of VU6001192,1 is a potent negative allosteric modulator (NAM) and showed high binding affinity for mGluR2 (IC50 = 26nM) than VU6001192 and high brain penetration. Moreover, 1 showed a suitable lipophilicity (cLogD = 3.12). Herein, we performed the chemical syntheses of unlabeled 1 and desmethyl phenol precursor, the radiosynthesis of [11C]1, and the in vitro and vivo specific binding studies in the rodent brain using autoradiography and PET. We also synthesized [11C]VU6001192 and compared its potentials as a PET tracer with [11C]1. Methods [11C]1 and [11C]VU6001192 were synthesized by the reaction of their corresponding desmethy precursors with [11C]methyl iodide. The distribution of radioactivity in mice was measured at different time points after injection of radiotracer. In vitro autoradiography, PET scan, and metabolite analysis were performed on rat brains. Results [11C]1 (7.4 ± 2.8 GBq; n = 8) and [11C]VU6001192 (3.2 ± 1.5 GBq; n = 5) were obtained from [11C]CO2 of 20–22 GBq with >98% radiochemical purity and 70–112 GBq/μmol molar activity. In vitro autoradiography showed that the distribution pattern of [11C]1 radioactivity was heterogeneous with high expression in the cerebral cortex, striatum, hippocampus, and cerebellum. This distribution pattern was consistent with the distribution of mGluR2 in the rat brain. The radioactivity was significantly reduced by self‐ or MNI‐137 (a mGluR2 NAM) blocking. In the mouse brain, the initial uptake of [11C]1 was 1.1%ID/g at 1 min. PET study showed that the uptake of radioactivity peaked at 2 min with a SUV of 0.72 in the cerebral cortex and rapidly decreased afterwards. Self‐blocking with 1 produced a fairly uniform distribution of radioactivity in all brain regions. The PET results suggest that a certain level of in vivo specific binding of [11C]1 could be found in the rat brain. The whole brain uptake increased 74% in Pgp/BCRP‐KO mice, compared to that in wild‐type mice (calculated from the area under curve). Metabolite analysis showed most radioactivity in the brain represented the unchanged [11C]1. On the other hand, PET with [11C]VU6001192 showed a very low brain uptake (SUV < 0.3). Conclusion In this study, we have synthesized [11C]1 as a new PET tracer with good radiochemical yield, high radiochemical purity, and high molar activity. While [11C]1 has limited potential as a PET tracer for the imaging of brain mGluR2, it can be used to develop new radiotracers with improved in vitro profiles and in vivo behaviors. REFERENCE Bollinger K. A., Felts A. S., Brassard C. J., et al. ACS Med. Chem. Lett. 2017, 8, 919–924. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | ISRS2019 | |||||
| 発表年月日 | ||||||
| 日付 | 2019-05-28 | |||||
| 日付タイプ | Issued | |||||
