Central 5-HT2A and D-2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men

It has been suggested that a combined blockade of 5-HT2A and D-2-dopamine receptors improves efficacy and reduces the risk for extrapyramidal symptoms when treating schizophrenic patients with antipsychotic drugs. ORG 5222 is a new potential antipsychotic drug which has high affinity for 5-HT2A, D-2-dopamine and alpha(1) adrenergic receptors in vitro. The objective of this study was to examine if ORG 5222 occupies 5-HT2A and D-2-dopamine receptors in human subjects in vivo. Central receptor occupancy was measured by positron emission tomography (PET) in three healthy subjects after sublingual administration of 100 mu g ORG 5222. [C-11]N-methylspiperone ([C-11] NMSP) was the radioligand used to measure 5-HT2A receptor binding in the neocortex and [C-11]raclopride to measure D-2-dopamine receptor binding in the striatum. The 5-HT2A occupancy was 15-30% and the D-2-dopamine receptor occupancy was 12-23%. The study con firms that ORG 5222 binds to 5-HT2A and D-2-dopamine receptors in human brain. Since receptor occupancy of ORG 5222 is rather low, doses higher than 100 mu g are suggested in future clinical trials to evaluate the antipsychotic drug effect of ORG 5222.