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Psychopharmacology (Berl). 2016 Oct;233(19-20):3503-12. doi: 10.1007/s00213-016-4382-y. Epub 2016 Aug 15.

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.

Author information

Department of Psychiatry, New York State Psychiatric Institute, Columbia University, 1051 Riverside Drive Unit 31, New York, NY, 10032, USA.
New York State Psychiatric Institute (NYSPI), Columbia University Medical Center, New York, NY, USA.
New York State Psychiatric Institute (NYSPI), Columbia University Medical Center, New York, NY, USA.
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.
Forest Research Institute, Jersey City, NJ, USA.
Pharmaceutical Product Development, LLC, Richmond, VA, 23230, USA.
Inncelerex, Jersey City, NJ, USA.
Gedeon Richter Plc., Budapest, Hungary.



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.


Antipsychotic; Cariprazine; Dopamine D2 receptor; Dopamine D3 receptor; Occupancy; Positron emission tomography; Schizophrenia; [11C]-(+)-PHNO

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Conflict of interest statement

Support for this research and publication was funded by Forest Laboratories, LLC, Jersey City, New Jersey, USA, an Allergan affiliate, and Gedeon Richter, Plc, Budapest, Hungary. Forest Laboratories and Gedeon Richter were involved in the study design, analysis, interpretation of data, and decision to present these results. Antonia Periclou, Suresh Durgam, and Nika Adham acknowledge a potential conflict of interest as employees of Forest Research Institute, an Allergan affiliate. Yih Lee, Parviz Ghahramani, and Ashok Rakhit acknowledge a potential conflict of interest as employees of Forest Research Institute at the time of the study. István Laszlovszky, Béla Kiss, and Margit Kapás acknowledge a potential conflict of interest as employees of Gedeon Richter Plc. Ragy Girgis has received research funding from Otsuka and Genentech. Mark Slifstein has served as a consultant to Amgen and has received research funding from Otsuka. Anissa Abi-Dargham has served as a consultant for Roche, Otsuka, Forum, and Amgen and has received research support from Takeda, Forest Laboratories, Pierre Fabre, and CHDI Foundation. Nabeel Nabulsi had received royalty payments from the University of Texas M.D. Anderson Cancer Center from patented work. Deepak D’Souza, Richard Carson, and Yiyun Huang have no disclosures to report pertaining to this work.

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