Autoradiographic localization of 5-HT2A receptors in the human brain using L3H]M100907 and [11C]M100907

M100907 (MDL 100907, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl] -4-piperidinemethanol) is a new selective antagonist of 5-HT2A receptors, The compound has been labeled with C-11 and proved useful for in vivo studies of 5-HT2A receptors using positron emission tomography (PET). In the present study the distribution of 5-HT2A receptors was examined in the postmortem human brain using whole hemisphere autoradiography and [H-3]M100907 and [C-11]M100907. The autoradiograms showed very dense binding to all neocortical regions, whereas the hippocampus was only weakly labeled with [H-3]M100907. Other central brain regions, such as the basal ganglia and thalamus, showed low [H-3]M100907 binding, reflecting low densities of 5-HT2A receptors. The cerebellum or structures of the brain stem were virtually devoid of 5-HT2A receptors. [C-11]M100907 gave images qualitatively similar to those of [H-3]M100907, although with lower spatial resolution. The labeling of human 5-HT2A receptors With [H-3]M100907 was inhibited by the addition of the 5-HT2A receptor blockers ketanserin or SCH 23390 (10 muM), leaving a very low background of nonspecific binding. The 5-HT1A receptor antagonist WAY-100635 and the D-2-dopamine receptor antagonist raclopride had no effect on the binding of [H-3]M100907. The selective labeling of 5-HT2A receptors with [H-3]M100907 clearly shows that this compound is suitable for further studies of the human 5-HT2A receptor subtype in vitro. The in vitro autoradiography of the distribution of 5-HT2A receptors obtained with radiolabeled M100907 provides detailed qualitative and quantitative information on the distribution of 5-HT2A-receptors in the human brain as well as reference information for the interpretation of previous initial results at much lower resolution in humans in vivo with PET and [C-11]M100907. (C) 2000 Wiley-Liss, Inc.