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 receptor antagonist [I-123]R93274 (123-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 tomography (SPECT) radiotracer to image 5-HT2A receptors in the living human brain. In this study, we characterized the brain uptake of [I-123]R93274 in baboons. Highest brain uptake was observed in cortical areas, while lower uptake was observed in the striatum and the cerebellum. Injection of pharmacological doses of the 5-HT2A receptor antagonist ketanserin resulted in reduction of cortical and striatal radioactivities to the level observed in the cerebellum. Injection of the selective dopamine D-2 receptor antagonist raclopride did not affect [I-123]R93274 brain uptake. Quantification of 5-HT2A receptors was achieved by measuring the binding potential of 5-HT2A receptors [I-123]R93274 (the binding potential is the product of the density and affinity of available receptors). Regional binding potential values were derived with a three-compartmental kinetic analysis of the time-activity curves in the brain and plasma. Binding potential values of 93 +/- 34 ml/g, 71 +/- 35 ml/g and 31 +/- 11 ml/g were measured in the occipital, temporal and striatal regions, respectively. Similar values were derived using a noncompartmental graphical analysis. These values were in accordance with the in vitro regional distribution of 5-HT2A receptors in primate brain. In conclusion, [I-123]R93274 allows visualization and quantification of 5-HT2A receptors in the baboon brain with SPECT. (C) 1997 Elsevier Science B.V. All rights reserved.