WEKO3
アイテム
Synthesis, pharmacology and preclinical evaluation of 11C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein
https://repo.qst.go.jp/records/49148
https://repo.qst.go.jp/records/4914803382cec-b28a-4346-98c5-fad1675c6f3e
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2018-08-10 | |||||
| タイトル | ||||||
| タイトル | Synthesis, pharmacology and preclinical evaluation of 11C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein | |||||
| 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_6501 | |||||
| 資源タイプ | journal article | |||||
| 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× Mori, Wakana× Zhang, Xiaofei× Yamasaki, Tomoteru× J. Dunn, Patrick× Zhang, Genwei× Fu, Hualong× Shao, Tuo× Zhang, Yiding× Hatori, Akiko× Ma, Longle× Fujinaga, Masayuki× Xie, Lin× Deng, Xiaoyun× Li, Hua× Yu, Qingzhen× Rong, Jian× Josephson, Lee× Jun-An, Ma× Shao, Yihan× Tomita, Susumu× Ming-Rong, Zhang× Liang, Huan× Mori, Wakana× Yamasaki, Tomoteru× Zhang, Yiding× Hatori, Akiko× Fujinaga, Masayuki× Xie, Lin× Ming-Rong, Zhang× Liang, Huan |
|||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | a-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are implicated in the pathology of neurological diseases such as epilepsy and schizophrenia. As pan antagonists for this target are often accompanied with undesired effects at high doses, one of the recent drug discovery approaches has shifted to subtype-selective AMPA receptor (AMPAR) antagonists, specifically, via modulating transmembrane AMPAR regulatory proteins (TARPs). The quantification of AMPARs by positron emission tomography (PET) would help obtain insights into disease conditions in the living brain and advance the translational development of AMPAR antagonists. Herein we report the design, synthesis and preclinical evaluation of a series of TARP γ-8 antagonists, amenable for radiolabeling, for the development of subtype-selective AMPA PET imaging agents. Based on the pharmacology evaluation, molecular docking studies and physiochemical properties, we have identified several promising lead compounds 3, 17–19 and 21 for in vivo PET studies. All candidate compounds were labeled with [11C]COCl2 in high radiochemical yields (13–31% RCY) and high molar activities (35–196 GBq/μmol). While tracers 30 ([11C]17) & 32 ([11C]21) crossed the blood-brain barrier and showed heterogeneous distribution in PET studies, consistent with AMPA TARP γ-8 expression, high nonspecific binding prevented further evaluation. To our delight, tracer 31 ([11C]3) showed good in vitro specific binding and characteristic high uptake in the hippocampus in rat brain tissues, which provides the guideline for further development of a new generation subtype selective TARP γ-8 dependent AMPA tracers. | |||||
| 書誌情報 |
European Journal of Medicinal Chemistry 巻 157, p. 898-908, 発行日 2018-08 |
|||||
| 出版者 | ||||||
| 出版者 | Elsevier | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 0223-5234 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1016/j.ejmech.2018.08.019 | |||||
