Occupancy of dopamine D 2 and D 3 and serotonin 5-HT 1A 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.