Preclinical evaluation of [123I]R93274 as a SPECT radiotracer for imaging 5-HT2A receptors

Studies in rodents have suggested that the radioiodinated 5-HT2A receptor antagonist [123I]R93274 (123-iodine-N-[(3-p-fluorophenyl-1-propyl)-4-methyl-4-piperidinyl]-4-ami no- 5-iodo-2-methoxybenzamide) (Kd = 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 [123I]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 D2 receptor antagonist raclopride did not affect [123I]R93274 brain uptake. Quantification of 5-HT2A receptors was achieved by measuring the binding potential of 5-HT2A receptors for [123I]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, [123I]R93274 allows visualization and quantification of 5-HT2A receptors in the baboon brain with SPECT.