Dopamine D2/3 receptor occupancy of apomorphine in the nonhuman primate brain—A comparative PET study with [11C]raclopride and [11C]MNPA

Binding studies in vitro have demonstrated that the dopamine D₂ receptor may exist in two affinity states for agonists. The high affinity state is thought to represent the functional state of the receptor and proportions might alter during disease. In vitro studies further indicate that agonists induce measurable D₂ receptor occupancy at clinically relevant concentrations but only when measured at the high affinity state. Recently developed PET‐radioligands, such as ¹¹C]MNPA, have now made it possible to directly study agonist binding in vivo. The aim of this study was to compare the inhibition by apomorphine of agonist and antagonist radioligand binding to D_2/3 receptors in vivo. A total of 36 PET measurements were performed with the D_2/3 antagonist ¹¹C]raclopride or the D_2/3 agonist ¹¹C]MNPA in two cynomolgus monkeys. On each study day, a baseline measurement was followed by two consecutive pretreatment studies with rising doses of apomorphine (0.01, 0.05, 0.15, 0.5, 1.0, and 3.0 mg/kg). Binding potential (BP_ND) values were calculated for the striatum with cerebellum as reference region. Apomorphine inhibited ¹¹C]raclopride and ¹¹C]MNPA binding in a dose‐dependent manner and to a similar extent. ID₅₀ and K_i values were 0.26 mg/kg and 29 ng/ml for ¹¹C]raclopride and 0.50 mg/kg and 31 ng/ml for ¹¹C]MNPA. The present observations do not support the existence of two affinity states in vivo. It might thus be speculated that all D_2/3 receptors are in the high affinity state at in vivo conditions. Synapse 63:378–389, 2009. © 2009 Wiley‐Liss, Inc.