Occupancy of dopamine D₂ and D₃ and serotonin 5-HT₁A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography.

Rationale: Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D(3) and D(2) receptors and moderate affinity to serotonin 5-HT(1A) receptors. Targeting receptors other than D(2) may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug.

Objectives: The objective of this study was to determine dopamine D(2)/D(3) and serotonin 5-HT(1A) receptor occupancy in monkey brain after the administration of cariprazine.

Methods: We examined three monkeys using the following PET radioligands: [(11)C]MNPA (an agonist at D(2) and D(3) receptors), [(11)C]raclopride (an antagonist at D(2) and D(3) receptors), and [(11)C]WAY-100635 (an antagonist at 5-HT(1A) receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose.

Results: We found that cariprazine occupied D(2)/D(3) receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT(1A) receptor occupancy was considerably lower compared with D(2)/D(3) occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei.

Conclusions: We conclude that cariprazine binds preferentially to dopamine D(2)/D(3) rather than to serotonin 5-HT(1A) receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.