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-HT1A 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-HT1A receptor occupancy in monkey brain after the administration of cariprazine. Methods We examined three monkeys using the following PET radioligands: [C-11]MNPA (an agonist at D-2 and D-3 receptors), [C-11]raclopride (an antagonist at D-2 and D-3 receptors), and [C-11]WAY-100635 (an antagonist at 5-HT1A 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 similar to 5% of receptors and the highest dose showing more than 90% occupancy. 5-HT1A receptor occupancy was considerably lower compared with D-2/D-3 occupancy at the same doses, with a maximal value of similar to 30% for the raphe nuclei. Conclusions We conclude that cariprazine binds preferentially to dopamine D-2/D-3 rather than to serotonin 5-HT1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.