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Synthesis and preclinical evaluation of 11C-labeled 1,3-dihydro-2H-benzo[d]imidazol-2-ones for development of TARP γ-8 dependent AMPAR PET tracers
https://repo.qst.go.jp/records/72840
https://repo.qst.go.jp/records/728408e2da75b-dab9-4406-8313-7c1945288c7e
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2018-06-29 | |||||
| タイトル | ||||||
| タイトル | Synthesis and preclinical evaluation of 11C-labeled 1,3-dihydro-2H-benzo[d]imidazol-2-ones for development of TARP γ-8 dependent AMPAR PET tracers | |||||
| 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 |
Chen, Zhen
× Chen, Zhen× Zhang, Xiaofei× SHAO, TUO× Shao, Yihan× Tomita, Susumu× Zhang, Ming-Rong× Liang, Huan× 張 明栄× 梁 歓 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: Transmembrane a-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory proteins are a new family of scaffolding proteins, which regulate the trafficking, gating, protein levels and pharmacology of AMPA receptors (AMPARs). The goal of the project was to establish a focused library of TARP γ-8 dependent AMPAR antagonists amenable for radiolabeling with carbon-11 or fluorine-18, and carry out preliminary in vivo evaluation for imaging TARP γ-8 by PET. Methods: A focused library of 1,3-dihydro-2H-benzo[d]imidazol-2-ones and benzo[d]thiazol-2(3H)-ones were synthesized based on lead AMPAR antagonist JNJ-55511118.[1] We designed PdCl2(dtbpf)-catalyzed cross-coupling of aryl boric acid 1 with 4-bromobenzene-1,2-diamine 2 to afford desired [1,1'-biaryl]-3,4-diamine precursors 3-10 in moderate to excellent yields (42-86%). The cyclization of diamine 3-10 was achieved by treatment with 1,1’-carbonyldiimidazole (CDI), thus delivering urea-type candidate AMPAR inhibitors 11-18 in 52-82% yields. The carbamothioate-type candidate AMPAR inhibitors 21-23 were also obtained in 62-83% yields over two steps via protection of 6-bromobenzo[d]thiazol-2(3H)-one 19 with Boc2O followed by coupling with aryl boric acid 1. The focused library of 1,3-dihydro-2H-benzo[d]imidazol-2-ones 11-18 and benzo[d]thiazol-2(3H)-ones 21-23 was then subjected to in vitropharmacological evaluation using calcium flux assay and molecular docking studies by AutoDock. The most promising compounds were radiolabeled at the 11C-carbonyl position using [11C]COCl2. Dynamic PET imaging studies were performed in SD rats in a Siemens Inveon scanner for 60 min. Results: The urea-type standard compounds 11-18 and carbamothioate-type candidates 21-23 were obtained in 31-83% yields over two steps. The labeling precursor diamine 3 and 10 was assembled in 42% and 86% yield, respectively. Preliminary pharmacological evaluation demonstrated compounds 11, 12 and 14 as promising candidates, which possessed high potency to TARP γ-8 with IC50 values between 10-20 nM and excellent subtype selectivity between γ-8 and γ-2 dependent AMPARs. The homology binding pocket between TARP γ-8 and candidate compounds was established using SWISS-MODEL, with the best hit, pdb 5kk2, as the building template, to study the molecular interaction.[2] The overall G-factor average of the model was -0.26, indicating reasonable normality. As proof of concept, [11C]11 was radiolabeled in 13.4% decay-corrected RCY relative to starting [11C]CO2 with high radiochemical purity (>99%) and high specific activity (196.6 GBq/μmol). No radiolysis of [11C]11 was detected up to 90 min after formulation (10% ethanol in saline). Dynamic PET studies of [11C]11 exhibited reasonable brain penetration (~0.8 SUV). Conclusion: We have established a small library of TARP γ-8 dependent AMPAR antagonists, and identified several lead molecules for in vivoevaluation. The radiosynthesis of [11C]11 was achieved in excellent yield, and in vivoPET study confirmed brain permeability of [11C]1. Further radiolabeling of 12 and 14, followed by blocking studies and radiometabolite analysis will be performed to develop new TARP γ-8 dependent AMPA receptor PET tracers. References: [1] J Pharmacol Exp Ther. 2016, 357, 394-414; [2] ACS Chem Neurosci., 2017, 8, 2631-2647. | |||||
| 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 | SNMMI 2018 Annual Meeting | |||||
| 発表年月日 | ||||||
| 日付 | 2018-06-25 | |||||
| 日付タイプ | Issued | |||||
