In vivo occupancy of D-2 dopamine receptors by nafadotride

Nafadotride has been proposed as a selective antagonist for the D-3 dopamine receptor. This drug has been shown to exhibit selectivity between D-2 and D-3 dopamine receptors in in vitro assay systems; however, the in vivo D-2/D-3 selectivity of the compound has not been determined. In this study, protection against inactivation by EEDQ was used as it measure of in vivo occupancy of D-2 receptors by behaviorally relevant doses of nafadotride (0.1-10 mg/kg, SC and IF) in adult, male Sprague-Dawley rats. Ex vivo [H-3]spiperone binding was then determined in striatal membranes. 1-Nafadotride (10 mg/kg) protected 71% of D-2 receptors after SC administration; 40% after IP administration. Protection of 13% of D-2 receptors teas observed at a dose of 3 mg/kg (SC). These data suggest that blockade of D-2 receptors contributes to the pharmacological effects of nafadotride when administered at doses above 1 mg/kg (SC) or 3 mg/kg (IP). (C) American College of Neuropsychopharmacology. Published by Elsevier Science Inc.