Autoradiographic localization of 5-HT2A receptors in the human brain using(LH)-H-3]M100907 and [C-11]M100907

M100907 (MDL 100907, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl )ethyl] -4-piperidinemethanol) is a new selective antagonist of 5-HT2A rece ptors, The compound has been labeled with C-11 and proved useful for in viv o 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]M100 907 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 tha lamus, showed low [H-3]M100907 binding, reflecting low densities of 5-HT2A receptors. The cerebellum or structures of the brain stem were virtually de void of 5-HT2A receptors. [C-11]M100907 gave images qualitatively similar t o those of [H-3]M100907, although with lower spatial resolution. The labeli ng of human 5-HT2A receptors With [H-3]M100907 was inhibited by the additio n of the 5-HT2A receptor blockers ketanserin or SCH 23390 (10 muM), leaving a very low background of nonspecific binding. The 5-HT1A receptor antagoni st WAY-100635 and the D-2-dopamine receptor antagonist raclopride had no ef fect on the binding of [H-3]M100907. The selective labeling of 5-HT2A recep tors with [H-3]M100907 clearly shows that this compound is suitable for fur ther studies of the human 5-HT2A receptor subtype in vitro. The in vitro au toradiography of the distribution of 5-HT2A receptors obtained with radiola beled M100907 provides detailed qualitative and quantitative information on the distribution of 5-HT2A-receptors in the human brain as well as referen ce information for the interpretation of previous initial results at much l ower resolution in humans in vivo with PET and [C-11]M100907. (C) 2000 Wile y-Liss, Inc.