title: Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO.
abstract: Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia.
  
  
  
  The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia.
  
  
  
  Using [(11)C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations.
  
  
  
  A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing.
  
  
  
  This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, Columbia University, 1051 Riverside Drive Unit 31, New York, NY, 10032, USA. ragygir@nyspi.columbia.edu.|New York State Psychiatric Institute (NYSPI), Columbia University Medical Center, New York, NY, USA. ragygir@nyspi.columbia.edu.
authors.forename: Ragy R
authors.initials: RR
authors.lastname: Girgis
authors.affiliation: New York State Psychiatric Institute (NYSPI), Columbia University Medical Center, New York, NY, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.affiliation: Clinical Neuroscience Research Unit (CNRU), Yale School of Medicine, New Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, Yale PET Center, New Haven, CT, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: D'Souza
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.|Pharmaceutical Product Development, LLC, Richmond, VA, 23230, USA.
authors.forename: Yih
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Periclou
authors.affiliation: Inncelerex, Jersey City, NJ, USA.
authors.forename: Parviz
authors.initials: P
authors.lastname: Ghahramani
authors.affiliation: Gedeon Richter Plc., Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Durgam
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Nika
authors.initials: N
authors.lastname: Adham
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Yale PET Center, New Haven, CT, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Yale PET Center, New Haven, CT, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Yale PET Center, New Haven, CT, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Gedeon Richter Plc., Budapest, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Gedeon Richter Plc., Budapest, Hungary.
authors.forename: Margit
authors.initials: M
authors.lastname: Kapás
authors.affiliation: New York State Psychiatric Institute (NYSPI), Columbia University Medical Center, New York, NY, USA.
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Rakhit
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists; D054333:Drug Partial Agonism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines / Q000378:metabolism* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; C581293:DRD2 protein, human; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D010078:Oxazines; D010879:Piperazines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C042631:naxagolide; C533287:cariprazine; D004298:Dopamine
keywords: Antipsychotic; Cariprazine; Dopamine D2 receptor; Dopamine D3 receptor; Occupancy; Positron emission tomography; Schizophrenia; [11C]-(+)-PHNO