Characterization of the radioactive metabolites of the 5-HT1A receptor radioligand, [O-methyl-C-11]WAY-100635, in monkey and human plasma by HPLC: Comparison of the behaviour of an identified radioactive metabolite with parent radioligand in monkey using PET

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 (t(1/2) = 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-C-11]WAY-lO0635 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-C-11]WAY-lO0635 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-C-11]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-C-11]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-ii 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.