Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene. clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT(2A) receptors and D-2-type receptors. Predominant 5HT(2A) receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D-2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D-3 and in particular D-4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT(2A) than for D-2 receptors. Subnanomolar affinity for human 5HT(2A) receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D-2 receptors, Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D-2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D-4 than for D-2 receptors. For most other compounds, D-4 affinity was only slightly lower than their D-2 affinity. Seroquel was totally devoid of D-4 affinity. None of the compounds had nanomolar affinity for D-1, receptors: their affinity for D-3 receptors was usually slightly lower than for D-2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone. sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT(2A) than D-2 receptors. Risperidone and ORG-5222 had 5HT(2A) versus D-2 potency ratio of about 20. Highest potency for 5HT(2A) receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT(2A) receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D-2 receptors. No regional selectivity for D-2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D-2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha(1) receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha(1) than D-2 receptors. Clozapine showed predominant occupancy of H-1 receptors and occupied cholinergic receptors with equivalent potency to D-2 receptors. A stronger predominance of 5HT(2A) versus D-2 receptor occupancy combined with a more gradual occupancy of D-2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT(2A) receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D-2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT(2A) and D-2 occupancy and the avoidance of D-2 receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.
