In vivo receptor occupancy of NRA0045, a putative atypical antipsychotic, in rats

We have previously reported that (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4 -(4-fluorophenyl)-4-oxobutyl]pyrrolidlin yl]thiazole (NRA0035) is a novel a ntipsychotic agent with affinities for dopamine D-4 5-hydroxytryptamine 2A (5-HT2A) and alpha(1) receptors. In the present study, in vivo receptor occ upancy of 5-HT2A, alpha(1) dopamine D-2 and D-3 receptors by NRA0045 was as sessed, based on in vivo and ex vivo receptor binding, and findings were co mpared to reference antipsychotic drugs (haloperidol, risperidone, clozapin e). Intraperitoneal administration of haloperidol highly occupied the dopam ine D-2 receptor in the striatum and nucleus accumbens, and alpha(1) adreno ceptors in the frontal cortex. Occupation of the 5-HT2A receptor in the fro ntal cortex and the dopamine D-3 receptor in the nucleus accumbens and isla nds of Cajella was moderate. By contrast, atypical antipsychotics such as r isperidone and clozapine dose-dependently occupied the 5-HT2A receptor in t he frontal cortex, with moderate to negligible occupancy of the D-2 recepto r in the striatum and the nucleus accumbens. Clozapine and risperidone also occupied the alpha(1) adrenoceptor in the frontal cortex, and clozapine di d not occupy the dopamine D-3 receptor. As seen with other atypical antipsy chotics, intraperitoneal administration of NRA0045 dose-dependently occupie d the 5-HT2A receptor and the alpha(1) adrenoceptor in the frontal cortex, while it was without effect on dopamine D-2 and D-3 receptors in the striat um, nucleus accumbens and islands of Cajella. Thus, the strong occupancy of 5-HT2A and alpha(1) receptors is involved in the pharmacological action of NRA0045. (C) 1999 Elsevier Science Ltd. All rights reserved.