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

合成了2-[4-苯基哌啶醇]环己醇（vesamicol）和2-[4-苯基哌啶醇]环己醇（vesamicol）和在4-苯基哌啶啶部分引入甲基的甲基维氨醇类似物在大鼠脑和肝细胞膜上与sigma受体（σ-1, σ-2）和囊泡乙酰胆碱转运体（VAChT）的结合特性。在竞争抑制研究中，(-)-o-methylvesamicol [(-)- omev] （Ki = 6.7 nM）和(-)-vesamicol （Ki = 4.4 nM）对VAChT具有高亲和力。（+）-p-甲基vesamicol [(+)-pMeV] （Ki = 3.0 nM）和SA4503 （Ki = 4.4 nM）作为正电子发射断层扫描（PET）的σ-1作图剂，对σ-1受体具有较高的亲和力。（+）-pMeV对σ-1受体（Ki = 3.0 nM）的结合亲和力比σ-2受体（Ki = 40.7 nM）高约13倍。（+）-pMeV （Ki = 199 nM）对VAChT的亲和力明显低于SA4503 （Ki = 50.2 nM）和氟哌啶醇（Ki = 41.4 nM）。结果表明，(-)- omev（13）与VAChT的结合特性与(-)-vesamicol相似，(+)- pmev（16）与σ-1受体的结合具有较高的亲和力。综上所述，(-)- omev和(+)- pmev（16）具有适合11C标记的甲基结构，不仅可能成为新的VAChT配体和新型σ受体配体，而且可能分别成为VAChT和σ-1受体放射体和正电子发射断层扫描（PET）的新靶化合物。

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.