Evaluation of [O-methyl-C-11]RS-15385-197 as a positron emission tomography radioligand for central alpha(2)-adrenoceptors

Carbon-11 labelled RS-15385-197 and its ethylsulphonyl analogue, RS-79948-1 97, were evaluated in rats as potential radioligands to image central alpha (2)-adrenoceptors in vivo. The biodistributions of both compounds were comp arable with that obtained in an earlier study using tritiated RS-79938-197 and were consistent with the known localisation of alpha(2)-adrenoceptors. The maxi mal signals (total to non-specific binding) were, however, reduced , in the order [C-11]RS-7994X-197 < [C-11]RS-15385-197 < [H-3]RS-79938-197, primarily due to the difference in radiolabel position (O-methyl for carbo n-11] compared with S-ethyl for tritium), This resulted in the in-growth of radiolabelled metabolites in plasma, which, in turn, contributed to the no n-specific component of brain radioactivity. Nonetheless, the signal ratio of similar to 5 for a receptor-dense tissue compared with the receptor-spar se cerebellum, at 90-120 min after radioligand injection, encouraged the de velopment, of [O-methyl-C-11]RS-15385-197 fur human positron emission tomog raphy (PET), Unfortunately, in two human PET scans teach of 90 min), brain extraction of the radioligand was minimal, with volumes of distribution mor e than an order of magnitude lower than that measured in rats. Following in travenous injection, radioactivity was retained in plasma and metabolism of the radiolabelled compound was very low. Retrospective measurements of in vitro plasma protein binding and in vivo brain uptake index (BUI) in rats d emonstrated a higher protein binding of the radioligand in human compared w ith rat plasma and a lower BUI in the presence of human plasma. It is feasi ble that a higher affinity of RS-15385-197 for human plasma protein compare d with receptor limited the transport of the radioligand, Although one of t he PET scans showed a slight heterogeneity in biodistribution of radioactiv ity which was consistent with the known localisation of alpha(2)-adretlocep tors in human brain, it was concluded that [O-methyl-C-11]RS- 15385-197 sho wed little promise for routine quantification of alpha(2)-adrenoceptors in man.