Central 5-HT2A and D2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men

Abstract

It has been suggested that a combined blockade of 5-HT_2A and D₂-dopamine receptors improves efficacy and reduces the risk for extrapyramidal symptoms when treating schizophrenic patients with antipsychotic drugs. ORG 5222 is a new potential anti-psychotic drug which has high affinity for 5-HT_2A, D₂-dopamine and α₁ adrenergic receptors in vitro. The objective of this study was to examine if ORG 5222 occupies 5-HT_2A and D₂-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 μg ORG 5222. [¹¹C]N-methylspiperone ([¹¹C] NMSP) was the radioligand used to measure 5-HT_2A receptor binding in the neocortex and [¹¹C]raclopride to measure D₂-dopamine receptor binding in the striatum. The 5-HT_2A occupancy was 15–30% and the D₂-dopamine receptor occupancy was 12–23%. The study confirms that ORG 5222 binds to 5-HT_2A and D₂-dopamine receptors in human brain. Since receptor occupancy of ORG 5222 is rather low, doses higher than 100 μg are suggested in future clinical trials to evaluate the antipsychotic drug effect of ORG 5222.