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

我们合成了甲基维沙米考类似物，并研究了2-[4-苯基哌啶]环己醇(维萨米考)和4-苯基哌啶部分引入甲基的2-[4-苯基哌啶]环己醇类似物与Sigma受体(σ-1，σ-2)以及大鼠脑和肝脏膜上的囊泡性乙酰胆碱转运体(VAChT)的结合特性。在竞争性抑制研究中，(-)-邻甲基维沙米考[(-)-o MeV](Ki=6.7 nM)和(-)-维沙米考(Ki=4.4 nM)对Vacht有较高的亲和力。()-对甲维西米考[()-pMeV](Ki=3.0nM)和SA4503(Ki=4.4nM)是正电子发射断层扫描σ-1标记剂，对σ-1受体有很高的亲和力。PMeV与σ-1受体的结合亲和力(Ki=3.0nM)是Sigma-2(σ-2)受体亲和力(Ki=40.7nM)的13倍。()-pMeV(Ki=199 nM)对Vacht的亲和力远低于SA4503(Ki=50.2 nM)和氟哌啶醇(Ki=41.4 nM)。这些结果表明，(-)-o MeV(13)与VAChT的结合特性与(-)-维沙米考相似，而()-pMeV(16)与σ-1受体具有高亲和力。综上所述，具有合适结构的(-)-o MeV和()-pMeV(16)不仅可能成为一种新的VAChT配体和一种新型的σ受体配体，而且还可能分别成为VAChT和σ-1受体放射治疗和正电子发射断层扫描的新靶点。

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.