title: 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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: Attila
authors.initials: A
authors.lastname: Horváth
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pásztor
authors.forename: Margó
authors.initials: M
authors.lastname: Kapás
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.forename: Sándor
authors.initials: S
authors.lastname: Farkas
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011485:Protein Binding; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D044282:Receptor, Serotonin, 5-HT1A; C533287:cariprazine