In vivo occupancy of D2 dopamine receptors by nafadotride

Nafadotride has been proposed as a selective antagonist for the D3 dopamine receptor. This drug has been shown to exhibit selectivity between D2 and D3 dopamine receptors in in vitro assay systems; however, the in vivo D2/D3 selectivity of the compound has not been determined. In this study, protection against inactivation by EEDQ was used as a measure of in vivo occupancy of D2 receptors by behaviorally relevant doses of nafadotride (0.1-10 mg/kg, s.c. and i.p.) in adult, male Sprague-Dawley rats. Ex vivo [3H]spiperone binding was then determined in striatal membranes, l-Nafadotride (10 mg/kg) protected 71% of D2 receptors after s.c. administration; 40% after i.p. administration. Protection of 13% of D2 receptors was observed at a dose of 3 mg/kg (s.c.). These data suggest that blockade of D2 receptors contributes to the pharmacological effects of nafadotride when administered at doses above 1 mg/kg (s.c.) or 3 mg/kg (i.p.).