Brain uptake and distribution of the dopamine D3/D2 receptor partial agonist [11C]cariprazine: An in vivo positron emission tomography study in nonhuman primates.

Cariprazine is a dopamine D₃/D₂ receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D₃ and D₂ receptors (with ∼10-fold higher in vitro affinity to D₃ vs. D₂ receptors) and with moderate affinity to 5-HT_1A receptors. The main objective of the present molecular imaging investigation was 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 D₂ and D₃ 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 [¹¹C]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 [¹¹C]cariprazine binds to dopamine D₃/D₂ receptors. Nondisplaceable binding potential (BP_ND) measurements, using a simplified reference tissue model and cerebellum as 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 D₃/D₂ receptors. Furthermore, in PET imaging [¹¹C]cariprazine can effectively visualize dopamine D₃/D₂ receptors in the nonhuman primate brain. Synapse 67:258-264, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]