Osman S, Lundkvist C, Pike V W, Halldin C, McCarron J A, Swahn C G, Farde L, Ginovart N, Luthra S K, Gunn R N, Bench C J, Sargent P A, Grasby P M
MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Nucl Med Biol. 1998 Apr;25(3):215-23. doi: 10.1016/s0969-8051(97)00206-0.
N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl)++ +cyclohexanecarboxamide (WAY-100635), labelled in its amido carbonyl group with 11C (t1/2 = 20.4 min), is a promising radioligand for the study of brain 5-HT1A receptors with positron emission tomography (PET). Thus, in PET experiments in six cynomolgus monkeys and seven healthy male volunteers, [carbonyl-11C]WAY-100635 was taken up avidly by brain. Radioactivity was retained in regions rich in 5-HT1A receptors, such as occipital cortex, temporal cortex and raphe nuclei, but cleared rapidly from cerebellum, a region almost devoid of 5-HT1A receptors. [Carbonyl-11C]WAY-100635 provides about 3- and 10-fold higher signal contrast (receptor-specific to nonspecific binding) than [O-methyl-11C]WAY-100635 in receptor-rich areas of monkey and human brain, respectively. To elucidate the effect of label position on radioligand behaviour and to aid in the future biomathematical interpretation of the kinetics of regional cerebral radioactivity uptake in terms of receptor-binding parameters, HPLC was used to measure [carbonyl-11C]WAY-100635 and its radioactive metabolites in plasma at various times after intravenous injection. Radioactivity cleared rapidly from monkey and human plasma. Parent radioligand represented 19% of the radioactivity in monkey plasma at 47 min and 8% of the radioactivity in human plasma at 40 min. [Carbonyl-11C]desmethyl-WAY-100635 was below detectable limits in monkey plasma and at most a very minor radioactive metabolite in human plasma. [11C]Cyclohexanecarboxylic acid was identified as a significant radioactive metabolite. In human plasma this maximally represented 21% of the radioactivity at 10 min after radioligand injection. All other major radioactive metabolites in monkey and human plasma were even more polar. No-carrier-added [carbonyl-11C]cyclohexanecarboxylic acid was prepared in the laboratory and after intravenous administration into cynomolgus monkey was shown with PET to give only a low uptake of radioactivity into brain tissue. The acid rapidly gave rise to several radioactive metabolites of higher polarity in plasma. The observed lack of any significant metabolism of [carbonyl-11C]WAY-100635 to highly lipophilic or pharmacologically potent radioactive compounds is consistent with its high signal contrast in primate brain.
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），其酰胺羰基用11C标记（半衰期 = 20.4分钟），是一种很有前景的用于正电子发射断层扫描（PET）研究脑5-HT1A受体的放射性配体。因此，在对6只食蟹猴和7名健康男性志愿者进行的PET实验中，[羰基-11C]WAY-100635被脑大量摄取。放射性保留在富含5-HT1A受体的区域，如枕叶皮质、颞叶皮质和中缝核，但从小脑迅速清除，小脑是一个几乎没有5-HT1A受体的区域。在猴和人脑富含受体的区域，[羰基-11C]WAY-100635分别比[O-甲基-11C]WAY-100635提供高约3倍和10倍的信号对比度（受体特异性结合与非特异性结合之比）。为了阐明标记位置对放射性配体行为的影响，并有助于将来根据受体结合参数对区域脑放射性摄取动力学进行生物数学解释，使用高效液相色谱法在静脉注射后不同时间测量血浆中[羰基-11C]WAY-100635及其放射性代谢物。放射性从猴和人的血浆中迅速清除。母体放射性配体在47分钟时占猴血浆放射性的19%，在40分钟时占人血浆放射性的8%。[羰基-11C]去甲基-WAY-100635在猴血浆中低于检测限，在人血浆中最多是一种非常少量的放射性代谢物。[11C]环己烷羧酸被鉴定为一种重要的放射性代谢物。在人血浆中，这在放射性配体注射后10分钟时最大占放射性的21%。猴和人血浆中的所有其他主要放射性代谢物极性更强。在实验室中制备了无载体添加的[羰基-11C]环己烷羧酸，静脉注射到食蟹猴体内后，PET显示脑组织对其放射性摄取很低。该酸在血浆中迅速产生几种极性更高的放射性代谢物。观察到[羰基-11C]WAY-100635没有任何显著代谢为高亲脂性或药理活性放射性化合物，这与其在灵长类动物脑中的高信号对比度一致。
