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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

  • 1Department of Psychiatry, New York State Psychiatric Institute, Columbia University, 1051 Riverside Drive Unit 31, New York, NY, 10032, USA. ragygir@nyspi.columbia.edu.
  • 2New York State Psychiatric Institute (NYSPI), Columbia University Medical Center, New York, NY, USA. ragygir@nyspi.columbia.edu.
  • 3New York State Psychiatric Institute (NYSPI), Columbia University Medical Center, New York, NY, USA.
  • 4Clinical Neuroscience Research Unit (CNRU), Yale School of Medicine, New Haven, CT, USA.
  • 5Department of Psychiatry, Yale University School of Medicine, Yale PET Center, New Haven, CT, USA.
  • 6Forest Research Institute, Jersey City, NJ, USA.
  • 7Pharmaceutical Product Development, LLC, Richmond, VA, 23230, USA.
  • 8Inncelerex, Jersey City, NJ, USA.
  • 9Gedeon Richter Plc., Budapest, Hungary.

Abstract

RATIONALE:

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.

OBJECTIVE:

The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

KEYWORDS:

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

PMID:
27525990
PMCID:
PMC5035321
DOI:
10.1007/s00213-016-4382-y
[PubMed - in process]
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