A study about "the early diagnosis of the Alzheimer's disease" by the new transporter mapping agent

新型转运蛋白定位剂的“阿尔茨海默病早期诊断”研究

• 批准号: 17591257
• 负责人: SHIBA Kazuhiro
• 金额: $ 2.24万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591257/
• 关键词: VAChT; Sigma receptor; Vesamicol; molecular Imaging agent; Alzheimer's disease; PET; ポジトロン核種

We synthesized methylvesamicol analogs and investigated the binding characteristics of 2-[4-phenylpiperidino]cyclohexanol (vesamicol) and methylvesamicol analogs, with a methyl group introduced into the 4-phenylpiperidine moiety, to sigma receptors (σ-1, σ-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (-)-o-methylvesamicol [(-)-oMeV] (Ki = 6.7 nM), as well as (-)-vesamicol (Ki = 4.4 nM) had a high affinity for VAChT. (+)-p-methylvesamicol [(+)-pMeV] (Ki = 3.0 nM), as well as SA4503 (Ki = 4.4 nM), reported as a σ-1 mapping agent for positron emission tomography (PET), had a high affinity for the σ-1 receptor. The binding affinity of (+)-pMeV for the σ-1 receptor (Ki = 3.0 nM), was about 13 times higher than the sigma-2 (σ-2) receptor (Ki = 40.7 nM). (+)-pMeV (Ki = 199 nM) had a much lower affinity for VAChT than SA4503 (Ki = 50.2 nM) and haloperidol (Ki = 41.4 nM). These results showed that the binding characteristics of (-)-oMeV (13) to VAChT were similar to that of (-)-vesamicol and, that (+)-pMeV (16) bound to the σ-1 receptor with high affinity. In conclusion, (-)-oMeV and (+)-pMeV(16), which had a suitable structure, with a methyl group for labeling with 11C, may become not only a new VAChT ligand and a new type of σ receptor ligand, respectively, but may also become a new target compound of VAChT and the σ-1 receptor radiolig and for positron emission tomography (PET), respectively.

我们合成了甲基维沙米考类似物，并研究了 2-[4-苯基哌啶基]环己醇（维沙考）和甲基维沙考类似物（将甲基引入 4-苯基哌啶部分）与 sigma 受体（σ-1、σ-2）和囊泡乙酰胆碱转运蛋白的结合特性 (VAChT) 存在于大鼠脑膜和肝膜中。在竞争性抑制研究中，(-)-o-甲基维沙考 [(-)-oMeV] (Ki = 6.7 nM) 以及 (-)-维沙考 (Ki = 4.4 nM) 对 VAChT 具有高亲和力。 (+)-p-甲基维沙米醇 [(+)-pMeV] (Ki = 3.0 nM) 以及 SA4503 (Ki = 4.4 nM) 被报道为正电子发射断层扫描 (PET) 的 σ-1 作图剂，对 σ-1 受体具有高亲和力。 (+)-pMeV 对 σ-1 受体 (Ki = 3.0 nM) 的结合亲和力比 sigma-2 (σ-2) 受体 (Ki = 40.7 nM) 高约 13 倍。 (+)-pMeV (Ki = 199 nM) 对 VAChT 的亲和力比 SA4503 (Ki = 50.2 nM) 和氟哌啶醇 (Ki = 41.4 nM) 低得多。这些结果表明，(-)-oMeV (13) 与 VAChT 的结合特性与 (-)-vesamicol 相似，并且 (+)-pMeV (16) 以高亲和力与 σ-1 受体结合。综上所述，具有合适结构且带有11C标记甲基的(-)-oMeV和(+)-pMeV(16)不仅可能分别成为新型VAChT配体和新型σ受体配体，而且还可能分别成为VAChT和σ-1受体放射配体以及正电子发射断层扫描(PET)的新靶标化合物。

项目成果

Synthesis and binding affinities of methylvasamical analogs for the acetylcholine transporter and sigma receptor.

乙酰胆碱转运蛋白和西格玛受体的甲基血管类似物的合成和结合亲和力。

• 发表时间: 2006
• 期刊: Bioorg. Med. Chem. 14
• 作者: Yamada;et al.;中嶋憲一;櫻井英幸;Kazuhiro Shiba
• 通讯作者: Kazuhiro Shiba

Synthesis and binding affinities of methylvasamicol analogs for the acetylcholine transporter and sigma receptor.

甲基凡沙米醇类似物对乙酰胆碱转运蛋白和西格玛受体的合成和结合亲和力。

• 期刊: Bioorg.Med.Chem. (印刷中)
• 作者: Kenichi Nakajima;Hideo Kusuoka;Shigeyuki Nishimura;Akira Yamashina;Tsunehiko Nishimura;Kazuhiro Shiba
• 通讯作者: Kazuhiro Shiba