Osman S, Lundkvist C, Pike V W, Halldin C, McCarron J A, Swahn C G, Ginovart N, Luthra S K, Bench C J, Grasby P M, Wikström H, Barf T, Cliffe I A, Fletcher A, Farde L
Cyclotron Unit, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Nucl Med Biol. 1996 Jul;23(5):627-34. doi: 10.1016/0969-8051(96)00061-3.
N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), labelled in the O-methyl group with carbon-11 (t1/2 = 20.4 min), is a promising radioligand for application with positron emission tomography (PET) to the study of 5-HT1A receptors in living human brain. An understanding of the metabolism of this new radioligand is crucial to the development of a biomathematical model for the interpretation of the kinetics of radioactivity uptake in brain in terms of receptor-binding parameters. After intravenous injection of [O-methyl-11C]WAY-100635 into humans, radioactivity was found to clear rapidly from blood and plasma. By using established methods for the analysis of radioactivity in plasma, it was found that intravenously injected [O-methyl-11C]WAY-100635 is rapidly metabolised to more polar radioactive compounds in a cynomolgus monkey and in humans. Thus, at 60 min postinjection, parent radioligand represented 40% and 5% of the radioactivity in monkey and human plasma, respectively. In monkey and human, one of the radioactive metabolites was identified as the descyclohexanecarbonyl analogue of the parent radioligand, namely [O-methyl-11C]WAY-100634. This compound is known to have high affinity for 5-HT1A receptors and alpha 1-adrenoceptors. In a PET experiment it was demonstrated that, after IV injection of [O-methyl-11C]WAY-100634 into a cynomolgus monkey, radioactivity was avidly taken up by brain. Uptake of radioactivity was higher in 5-HT1A receptor-rich frontal cortex than in cerebellum, which is devoid of 5-HT1A receptors. Polar radioactive metabolites appeared in plasma. The results suggest that the use of WAY-100635 labelled with carbon-11 in its cyclohexanecarbonyl moiety may provide enhanced signal contrast in PET studies and a possibility to develop a simple biomathematical model for regional brain radioactivity uptake.
N-（2-（4-（2-甲氧基苯基）-1-哌嗪-1-基）乙基）-N-（2-吡啶基）环己烷甲酰胺（WAY-100635），其O-甲基用碳-11标记（半衰期t1/2 = 20.4分钟），是一种很有前景的放射性配体，可用于正电子发射断层扫描（PET）研究活体人脑中的5-HT1A受体。了解这种新型放射性配体的代谢情况对于建立生物数学模型至关重要，该模型可根据受体结合参数解释脑中放射性摄取的动力学。在给人类静脉注射[O-甲基-11C]WAY-100635后，发现放射性物质迅速从血液和血浆中清除。通过使用已建立的分析血浆中放射性的方法，发现在食蟹猴和人类中，静脉注射的[O-甲基-11C]WAY-100635会迅速代谢为极性更强的放射性化合物。因此，在注射后60分钟时，母体放射性配体在猴和人血浆中的放射性分别占40%和5%。在猴和人中，一种放射性代谢物被鉴定为母体放射性配体的去环己烷羰基类似物，即[O-甲基-11C]WAY-100634。已知该化合物对5-HT1A受体和α1-肾上腺素能受体具有高亲和力。在一项PET实验中表明，给食蟹猴静脉注射[O-甲基-11C]WAY-100634后，脑中会大量摄取放射性物质。富含5-HT1A受体的额叶皮质中的放射性摄取高于缺乏5-HT1A受体的小脑。极性放射性代谢物出现在血浆中。结果表明，在其环己烷羰基部分用碳-11标记的WAY-100635可能会在PET研究中提供增强的信号对比度，并有可能建立一个简单的生物数学模型来解释局部脑放射性摄取情况。
