PRECLINICAL EVALUATION OF [I-123] R93274 AS A SPECT RADIOTRACER FOR IMAGING 5-HT2A RECEPTORS

Studies in rodents have suggested that the radioiodinated 5-HT2A recep tor antagonist [I-123]R93274 -iodine-N-[(3-p-fluorophenyl-1-propyl)-4- methyl-4- piperindinyyl]-4-amino-5-indo-2-methoxybenzamide) (K-d = 0.1 nM) might be a promising single photon emission computerized tomograp hy (SPECT) radiotracer to image 5-HT2A receptors in the living human b rain. In this study, we characterized the brain uptake of [I-123]R9327 4 in baboons. Highest brain uptake was observed in cortical areas, whi le lower uptake was observed in the striatum and the cerebellum. Injec tion of pharmacological doses of the 5-HT2A receptor antagonist ketans erin resulted in reduction of cortical and striatal radioactivities to the level observed in the cerebellum. Injection of the selective dopa mine D-2 receptor antagonist raclopride did not affect [I-123]R93274 b rain uptake. Quantification of 5-HT2A receptors was achieved by measur ing the binding potential of 5-HT2A receptors [I-123]R93274 (the bindi ng potential is the product of the density and affinity of available r eceptors). Regional binding potential values were derived with a three -compartmental kinetic analysis of the time-activity curves in the bra in and plasma. Binding potential values of 93 +/- 34 ml/g, 71 +/- 35 m l/g and 31 +/- 11 ml/g were measured in the occipital, temporal and st riatal regions, respectively. Similar values were derived using a nonc ompartmental graphical analysis. These values were in accordance with the in vitro regional distribution of 5-HT2A receptors in primate brai n. In conclusion, [I-123]R93274 allows visualization and quantificatio n of 5-HT2A receptors in the baboon brain with SPECT. (C) 1997 Elsevie r Science B.V. All rights reserved.