Receptor occupancy by ritanserin and risperidone measured using ex vivo autoradiography

In this study, autoradiographical techniques are introduced to investigate the occupancy of serotonin 5-HT2, dopamine D2 and alpha 1-adrenergic receptors after the in vivo administration of ritanserin, a selective, potent and long-acting 5-HT2 antagonist and of risperidone, a very potent 5-HT2 antagonist and potent D2 and alpha 1 antagonist. Unoccupied 5-HT2 and alpha 1-receptors were labelled with [125I]7-amino-8-iodoketanserin ([125I]AMIK) and D2 receptors with [125I]iodosulpride in horizontal rat brain section. Receptor occupancy by the drugs was quantified by image analysis of the autoradiograms. Ritanserin produced 50% occupancy of the 5-HT2 receptors at a dose of 0.02 mg/kg s.c., while at 40 mg/kg s.c. ritanserin still did not occupy 50% of the D2 and alpha 1 receptors. Risperidone occupied 50% of the 5-HT2, alpha 1 and D2 receptors at 0.0075, 0.32 and 2.5 mg/kg s.c., respectively. Ex vivo autoradiography was found to be applicable where radioligand binding techniques using brain homogenates had failed for the study of ex vivo receptor occupancy due to rapid drug dissociation. Ex vivo autoradiography is hitherto the sole technique which allowed the measurement of alpha 1 receptor occupancy by risperidone after in vivo administration of the drug.