CHARACTERIZATION OF THE APPEARANCE OF RADIOACTIVE METABOLITES IN MONKEY AND HUMAN PLASMA FROM THE 5-HT1A RECEPTOR RADIOLIGAND, [CARBONYL-C-11]WAY-100635 - EXPLANATION OF HIGH SIGNAL CONTRAST IN PET AND AN AID TO BIOMATHEMATICAL MODELING

in-1-yl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (WAY-100635), label led in its amido carbonyl group with C-11 (t(1/2) = 20.4 min), is a pr omising radioligand for the study of brain 5-HT1A receptors with posit ron emission tomography (PET). Thus, in PET experiments in six cynomol gus monkeys and seven healthy male volunteers, [carbonyl-C-11]WAY-1006 35 was taken up avidly by brain, Radioactivity was retained in regions rich in 5-HT1A receptors, such as occipital cortex, temporal cortex a nd raphe nuclei, but cleared rapidly from cerebellum, a region almost devoid of 5-HT1A receptors. [Carbonyl-C-11]WAY-100635 provides about 3 - and 10-fold higher signal contrast (receptor specific to nonspecific binding) than [O-methyl-C-11]WAY-100635 in receptor-rich areas of mon key and human brain, respectively. To elucidate the effect of label po sition on radioligand behaviour and to aid in the future biomathematic al interpretation of the kinetics of regional cerebral radioactivity u ptake in terms of receptor-binding parameters, HPLC was used to measur e [carbonyl-C-11]WAY-100635 and its radioactive metabolites in plasma at various times after intravenous injection. Radioactivity cleared ra pidly from monkey and human plasma. Parent radioligand represented 19% of the radioactivity in monkey plasma at 47 min and 8% of the radioac tivity in human plasma at 40 min. [Carbonyl-C-11]desmethyl-WAY-100635 was below detectable limits in monkey plasma and at most a very minor radioactive metabolite in human plasma. [C-11]Cyclohexanecarboxylic ac id was identified as a significant radioactive metabolite. In human pl asma this maximally represented 21% of the radioactivity at 10 min aft er radioligand injection. All other major radioactive metabolites in m onkey and human plasma were even more polar. No-carrier-added [carbony l-C-11]cyclohexanecarboxylic acid was prepared in the laboratory and a fter 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 po larity in plasma. The observed lack of any significant metabolism of [ carbonyl-C-11]WAY-100635 to highly lipophilic or pharmacologically pot ent radioactive compounds is consistent with its high signal contrast in primate brain. (C) 1998 Elsevier Science Inc.