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

• Published in: Psychopharmacologia Vol. 218; no. 3; pp. 579 - 587
• Main Authors: Seneca, Nicholas, Finnema, Sjoerd J., Laszlovszky, István, Kiss, Béla, Horváth, Attila, Pásztor, Gabriella, Kapás, Margó, Gyertyán, István, Farkas, Sándor, Innis, Robert B., Halldin, Christer, Gulyás, Balázs
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.12.2011; Springer
• Subjects: Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Dose-Response Relationship, Drug; Macaca fascicularis; Medical sciences; Neuropharmacology; Neurosciences; Original Investigation; Pharmacology. Drug treatments; Pharmacology/Toxicology; Piperazines - administration & dosage; Piperazines - metabolism; Piperazines - pharmacology; Positron-Emission Tomography; Protein Binding; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptor, Serotonin, 5-HT1A - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - metabolism; Nonhuman primate brain; Serotonin 5-HT; Positron emission tomography (PET); Dopamine D; Cariprazine; Receptor occupancy; Neuroleptic; Psychotropic; Central nervous system; Monkey; Pharmacotherapy; Encephalon; 5-HT1A Serotonine receptor; Primates; Antipsychotic; Biological receptor; Drug; Dopamine; Serotonin; Catecholamine; Vertebrata; Mammalia; Treatment; Animal; Neurotransmitter; Piperazine derivatives; Positron emission tomography; Emission tomography
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-011-2343-z

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.