Preferential binding to dopamine D(3) over D(2) receptors by cariprazine in patients with schizophrenia using PET with the D(3)/D(2) receptor ligand [(11)C]-(+)-PHNO

RATIONALE: Second-generation antipsychotics occupy dopamine D(2) 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 D(3) 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 D(3) receptor has become a target for treating negative symptoms in combination with D(2) 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 D(2) and D(3) 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 D(3) and D(2) receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D(3) over D(2) receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC(50) (D(3) = 3.84 nM and D(2) = 13.03 nM) in plasma after 2 weeks of dosing. CONCLUSION: This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D(3)-preferring dual D(3)/D(2) receptor partial agonist. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00213-016-4382-y) contains supplementary material, which is available to authorized users.