Brain Uptake and Distribution of the Dopamine D_3/D_2 Receptor Partial Agonist [~(11)C]Cariprazine: An In Vivo Positron Emission Tomography Study in Nonhuman Primates

摘要

Cariprazine is a dopamine D_3/D_2 receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D_3 and D_2 receptors (with ~10-fold higher in vitro affinity to D_3 vs. D_2 receptors) and withmoderate affinity to 5-HT_(1A) receptors. Themain objective of the present molecular imaging investigationwas to evaluate the uptake and reversible binding of 11-C labeled cariprazine in the nonhuman primate brain, in relation to the known distributions of dopamine D_2 and D_3 receptors.We examined the brains of two cynomolgus monkeys at baseline condition as well as during a pharmacological blocking condition, using unlabeled cariprazine or raclopride as blockers before injection of [~(11)C]cariprazine. Of the total injected radioactivity, ~7% entered the brain and ~3–4% remained in the brain after 90 min, indicating good blood brain barrier penetration and slow washout. It was possible to block cariprazine binding with unlabeled cariprazine and raclopride indicating that [~(11)C]cariprazine binds to dopamine D_3/D_2 receptors. Nondisplaceable binding potential (BP_(ND))measurements, using a simplified reference tissuemodel and cerebellumas the reference region, yielded values of ~1.5 and 0.3 in the striatum and thalamus, respectively. Striatum BP_(ND) values were reduced by 80 and 85% following pretreatment with 0.1 mg/kg IV injection of unlabeled cariprazine and 1 mg/kg IV injection of unlabeled raclopride, respectively. The data confirm that cariprazine, a novel antipsychotic drug candidate, enters the nonhuman primate brain readily and binds to dopamine D_3/D_2 receptors. Furthermore, in PET imaging [~(11)C]cariprazine can effectively visualize dopamine D_3/D_2 receptors in the nonhuman primate brain. Synapse 67:258–264, 2013.