[H]WAY–100635 for 5–HT1A receptor autoradiography in human brain: a comparison with [H]8–OH–DPAT and demonstration of increased binding in the frontal cortex in schizophrenia

WAY–100635 is the first selective, silent 5–HT_1A (5-hydroxytryptamine_1A, serotonin-1A) receptor antagonist. We have investigated the use of ³H]WAY–100635 as a quantitative autoradiographic ligand in post-mortem human hippocampus, raphe and four cortical regions, and compared it with the 5–HT_1A receptor agonist, ³H]8–OH–DPAT. Saturation studies showed an average Kd for ³H]WAY–100635 binding in hippocampus of 1.1 nM. The regional and laminar distributions of ³H]WAY–100635 binding and ³H]8–OH–DPAT binding were similar. The density of ³H]WAY–100635 binding sites was 60–70% more than that of ³H]8–OH–DPAT in all areas examined except the cingulate gyrus where it was 165% higher. ³H]WAY–100635 binding was robust and was not affected by the post-mortem interval, freezer storage time or brain pH (agonal state). Using ³H]WAY–100635, we confirmed an increase of 5–HT_1A receptor binding sites in the frontal cortex in schizophrenia, previously demonstrated with ³H]8–OH–DPAT. Compared to ³H]8–OH–DPAT, ³H]WAY–100635 has two advantages: it has a higher selectivity and affinity for the 5–HT_1A receptor, and it recognizes 5–HT_1A receptors whether or not they are coupled to a G-protein, whereas ³H]8–OH–DPAT primarily detects coupled receptors. Given these considerations, the ³H]WAY–100635 binding data in schizophrenia clarify two points. First, they indicate that the elevated ³H]8–OH–DPAT binding seen in the same cases is attributable to an increase of 5–HT_1A receptors rather than any other binding site. Second, the enhanced ³H]8–OH–DPAT binding in schizophrenia reflects an increased density of 5–HT_1A receptors, not an increased percentage of 5–HT_1A receptors which are G-protein-coupled. We conclude that ³H]WAY–100635 is a valuable autoradiographic ligand for the qualitative and quantitative study of 5–HT_1A receptors in the human brain.