Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan.
Bioorg Med Chem. 2012 Aug 15;20(16):4936-41. doi: 10.1016/j.bmc.2012.06.040. Epub 2012 Jun 29.
A series of vesamicol analogues, o-iodo-trans-decalinvesamicol (OIDV) or o-bromo-trans-decalinvesamicol (OBDV), were synthesized and their affinities to vesicular acetylcholine transporter (VAChT) and σ receptors (σ-1, σ-2) were evaluated by in vitro binding assays using rat cerebral or liver membranes. OIDV and OBDV showed greater binding affinity to VAChT (K(i) = 20.5 ± 5.6 and 13.8 ± 1.2 nM, respectively) than did vesamicol (K(i) = 33.9 ± 18.1 nM) with low affinity to σ receptors. A saturation binding assay in rat cerebral membranes revealed that [(125)I]OIDV had a single high affinity binding site with a K(d) value of 1.73 nM and a B(max) value of 164.4 fmol/mg protein. [(125)I]OIDV revealed little competition with inhibitors, which possessed specific affinity to each σ (σ-1 and σ-2), serotonin (5-HT(1A) and 5-HT(2A)), noradrenaline, and muscarinic acetylcholine receptors. In addition, BBB penetration of [(125)I]OIDV was verified in in vivo. The results of the binding studies indicated that OIDV and OBDV had great potential to be VAChT imaging probes with high affinity and selectivity.
一系列的维拉沙米醇类似物，邻碘-trans-去甲维拉沙米醇（OIDV）或邻溴-trans-去甲维拉沙米醇（OBDV）被合成出来，并通过使用大鼠脑或肝膜的体外结合测定来评估它们对囊泡乙酰胆碱转运体（VAChT）和σ受体（σ-1，σ-2）的亲和力。OIDV 和 OBDV 对 VAChT 的结合亲和力大于维拉沙米醇（K(i)分别为 20.5 ± 5.6 和 13.8 ± 1.2 nM，而维拉沙米醇为 33.9 ± 18.1 nM），对 σ 受体的亲和力较低。在大鼠脑膜的饱和结合测定中，[(125)I]OIDV 具有单一的高亲和力结合位点，K(d)值为 1.73 nM，B(max)值为 164.4 fmol/mg 蛋白。[(125)I]OIDV 与抑制剂的竞争很少，这些抑制剂对每种 σ（σ-1 和 σ-2）、血清素（5-HT(1A)和 5-HT(2A)）、去甲肾上腺素和毒蕈碱乙酰胆碱受体具有特异性亲和力。此外，在体内还验证了 [(125)I]OIDV 的 BBB 穿透性。结合研究的结果表明，OIDV 和 OBDV 具有成为高亲和力和选择性的 VAChT 成像探针的巨大潜力。
