Efange S M, Michelson R H, Knusel B, Hefti F, Boudreau R J, Thomas J R, Tennison J R
Department of Radiology, University of Minnesota, Minneapolis 55455.
Nucl Med Biol. 1993 May;20(4):527-38. doi: 10.1016/0969-8051(93)90083-7.
Three iodinated benzamides, 5-7, analogues of the potent acetylcholinesterase inhibitor 1-benzyl-4-[N-[4'-(benzylsulfonyl) benzoyl-N-methylamino]ethyl]piperidine (2), were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, receptor screening revealed that compounds 5-7 exhibit nanomolar affinity for the sigma binding site. Both [125I]5 and [125I]7 were synthesized and evaluated in rats. Following the intravenous administration of [125I]5 into rats, 1.59% of the injected dose was found in the rat brain within 5 min. The level of radioactivity in the brain remained steady for 2 h, the duration of the study. In contrast, 0.42% of the injected dose was detected in the rat brain following the i.v. injection of [125I]7. Coadministration of either [125I]5 or [125I]7 with 0.5 mumol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [123I]5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [123I]5 may be potentially useful for studying sigma receptor distribution in the human brain.
合成了三种碘化苯甲酰胺（5 - 7），它们是强效乙酰胆碱酯酶抑制剂1 - 苄基 - 4 - [N - [4' - （苄基磺酰基）苯甲酰基 - N - 甲基氨基]乙基]哌啶（2）的类似物，并作为潜在的抗胆碱酯酶药物进行了评估。发现所有这三种化合物的效力比母体化合物低三个数量级。然而，受体筛选显示化合物5 - 7对σ结合位点表现出纳摩尔亲和力。合成了[125I]5和[125I]7并在大鼠中进行了评估。给大鼠静脉注射[125I]5后，在5分钟内大鼠脑中发现了1.59%的注射剂量。在研究持续的2小时内，脑中的放射性水平保持稳定。相比之下，静脉注射[125I]7后，在大鼠脑中检测到0.42%的注射剂量。将[125I]5或[125I]7与0.5μmol/kg的氟哌啶醇共同给药导致大鼠脑中放射性水平降低56 - 73%，这表明这些化合物在体内与σ结合位点结合。用[123I]5进行的平面成像研究显示，放射性在猴脑中显著积累，半衰期为6小时。化合物[123I]5可能对研究人脑中σ受体分布有潜在用途。
