AUTORADIOGRAPHIC LOCALIZATION OF 5-HT1A RECEPTORS IN THE POSTMORTEM HUMAN BRAIN USING [H-3] WAY-100635 AND [C-11] WAY-100635

The distribution of 5-HT1A receptors was examined in the post-mortem h uman brain using whole hemisphere autoradiography and the selective 5- HT1A receptor antagonist [H-3]WAY-100635 zinyl)ethyl)-N-(2-pyridinyl)c yclohexanecarboxamide trihydrochloride). The autoradiograms showed ver y dense binding to hippocampus, raphe nuclei and neocortex. The labeli ng in neocortex was slightly lower than in the hippocampus and was mai nly at superficial layers, although a faintly labeled band could be se en in deeper neocortical layers. Other regions, such as the amygdala, septum and claustrum, showed low densities of [H-3]WAY-100635 binding, reflecting low densities of 5-HT1A receptors. The labeling was very l ow in basal ganglia, such as nucleus caudatus and putamen, in cerebell um or in structures of the brain stem except in the raphe nuclei. The labeling of human 5-HT1A receptors with [H-3]WAY-100635 was antagonize d by the addition of the 5-HT1A receptor ligands, 5-HT, buspirone, pin dolol or 8-OH-DPAT (10 mu M) leaving a very low background of non-spec ific binding. Saturation analysis of semiquantitative data from severa l human regions indicated that [H-3]WAY-100635 has a K-d of approximat ely 2.5 nM. The selective labeling of 5-HT1A receptors, with [H-3]WAy- 100635 clearly show that this compound is useful for further studies o f the human 5-HT1A receptor subtype in vitro. [C-11]WAY-100635 is used for the characterization of 5-HT1A receptors with positron emission t omography (PET). WAY-100635 was also radiolabeled with the short-lived positron-emitting radionuclide carbon-11 (t(1/2)=20 min) and used for in vitro autoradiography on human whole hemisphere cryosections. [C-1 1]WAY-100635 gave images qualitatively similar to those of [H-3]WAY-10 0635, although with a lower resolution. Thus, the hippocampal formatio n was densely labeled, with lower density in the neocortex. Buspirone, pindolol or 8-OH-DPAT (10 mu M), blocked all binding of [C-11]WAY-100 635. The in vitro autoradiography of the distribution of 5-HT1A recept ors obtained with radiolabeled WAY-100635 provide detailed qualitative and quantitative information on the distribution of 5-HT1A-receptors in the human brain. Moreover, the studies give reference information f or the interpretation of previous initial results at much lower resolu tion in humans with PET and [C-11]WAY-100635. These data provide a str ong basis for expecting [C-11]WAY-100635 to behave as a highly selecti ve radioligand in vivo.