In vivo occupation of dopamine D1, D2 and serotonin (5-HT)2A receptors by a novel antipsychotic drug, SM-9018 (perospirone hydrochloride; cis-N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride) and its major metabolite (ID-15036; N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1-hydroxy-1,2-cyclohexanedicarboximide) was measured in rat brain using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist, at these receptor sites. SM-9018 and its metabolite, ID-15036, dose-dependently reversed EEDQ-induced 5-HT2A and D2 receptor inactivation, but not D1 receptor inactivation. At lower doses (0.1 mg/kg i.p.), SM-9018 showed a preferential occupation of the 5-HT2A receptors, with only a small effect on the D2 receptors; while at higher doses (1.0 and 5.0 mg/kg i.p.), it was nearly equipotent in its occupation of both the D2 (77.8%) and the 5-HT2A receptors (78.6%). On the other hand, ID-15036 was more potent in occupying the 5-HT2A than the D2 receptors even at higher doses (1.0 and 5.0 mg/kg i.p.). We previously reported that atypical antipsychotic drugs, such as clozapine, were characterized by a high occupancy of the 5-HT2A receptors, with a low or minimum occupancy of the D2 receptors in vivo. The present study suggests that SM-9018 and its metabolite ID-15036 show a preferential tendency to occupy 5-HT2A receptors, and that the clozapine-like atypical properties of SM-9018 may be due to some pharmacological action of both the SM-9018 itself and its metabolite, ID-15063.