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Development and preliminary evaluations of novel PET tracers for imaging TARP γ-8 receptors
https://repo.qst.go.jp/records/86446
https://repo.qst.go.jp/records/864460bd4f763-1842-43eb-8f11-76c5f8ad82df
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2022-06-20 | |||||
| タイトル | ||||||
| タイトル | Development and preliminary evaluations of novel PET tracers for imaging TARP γ-8 receptors | |||||
| 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 |
Yu, Qingzhen
× Yu, Qingzhen× Katsushi, Kumata× Rong, Jian× Zhang, Ming-Rong× Liang, Steven× Katsushi, Kumata× Zhang, Ming-Rong |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Purpose/Background: AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor is an important protein in humans that is implicated in the increased risk of central nervous system (CNS) diseases including epilepsy and schizophrenia. Transmembrane AMPA receptor regulatory proteins subtype γ-8 (TARP γ-8) exhibits regiospecific expression in the brain, which could serve as a potential therapeutic target for CNS disorders with high selectivity. TARP γ-8 dependent AMPA receptors enrich primarily in the hippocampus. Through our previous in vitro studies, 6-(2-cyclobutyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one (compound 8, IC50 value of 0.02) and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-methyl-3H-imidazo[4,5-b]pyridine (compound 15, IC50 value of 1.26) from their categories were screened out as two potent and selective TARP γ-8 antagonist. Herein we report the radiosynthesis of their 11C-isotopologue ([11C]8 and [11C]15) and the preliminary evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo by positron emission tomography (PET). Methods: Radiosynthesis of two potential PET tracers [11C]8 and [11C]15, and synthesis of the corresponding precursors 22 and 27 were carried out as shown in Figure 1A. The reactions between [11C]CH3I and precursor 22 or 27 were carried out by heating a mixture of the precursor (0.8 mg), [11C]CH3I, Pd2(dba)3 (0.2 mg), P(o-tol)3 (6.0 mg), CuBr (1.0 mg) and K2CO3 (1.0 mg) in DMF (0.45 mL) at 130 oC for 5 min. As a result, [11C]8 and [11C]15 were obtained in an average radiochemical yield (RCY) of 9% and 22%, respectively (relative to [11C]CO2, decay corrected) with both high radiochemical purity (>99%) and excellent molar activity (>150 GBq/μmol at the end of synthesis (EOS)) with total synthesis time 27 minutes. Both radiotracers [11C]8 and [11C]15 exhibited excellent in vitro stability up to 90 min after formulation. The novel radiosynthesis, combined with high radiochemical purity and molar activities of [11C]8 and [11C]15 prompted us to perform the subsequent PET evaluation studies. Results: The radioligand [11C]8 and [11C]15 were synthesized in 9% and 22% decay-corrected radiochemical yield (RCY) respectively, based on the starting [11C]CO2 at the end-of-synthesis with >99% radiochemical purity (n = 5). Both of their molar activities were greater than 150 GBq/µmol (4.1 Ci/µmol). No sign of radiolysis was observed up to 90 min after re-formulation for both of [11C]8 and [11C]15. In PET studies, the radioligand [11C]8 failed to penetrate the BBB with no significant heterogeneous distribution in the hippocampus, frontal cortex, and cerebellum was observed in the baseline PET study. [11C]15 exhibited improved BBB penetration with great heterogeneous regional distribution pattern (high uptake in hippocampus while low uptake in cerebellum). The dramatic reduction of bound signals of [11C]15 in blocking studies were observed as well. These collective results indicated excellent in vivo binding specificity of [11C]15 rather than [11C]8 toward TARP γ-8, indicating [11C]15 would be a potential PET tracer for the clinical translation. Conclusion: We have evaluated the radiochemical method to prepare 11C-labeled labeled TARP ɣ-8 antagonists (compound 8 and 15) based on Stille coupling-based labeling methodology. Ultimately, the desired compounds [11C]8 and [11C]15 were labeled by [11C]CH3I in high radiochemical yield (9% and 22% respectively), high molar activity (>150 GBq/μmol) and high radiochemical purity (>99%). Besides, the PET studies of [11C]15 showed higher in vivo binding specificity toward TARP γ-8 in hippocampus than [11C]8, indicating its potential in clinical translation. |
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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 | SNMMI2022 | |||||
| 発表年月日 | ||||||
| 日付 | 2022-06-11 | |||||
| 日付タイプ | Issued | |||||
