Nicholas Seneca

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

RationaleCariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D3 and D2 receptors and moderate affinity to serotonin 5-HT1A receptors. Targeting receptors other than D2 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.ObjectivesThe objective of this study was to determine dopamine D2/D3 and serotonin 5-HT1A receptor occupancy in monkey brain after the administration of cariprazine.MethodsWe examined three monkeys using the following PET radioligands: [11C]MNPA (an agonist at D2 and D3 receptors), [11C]raclopride (an antagonist at D2 and D3 receptors), and [11C]WAY-100635 (an antagonist at 5-HT1A 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.ResultsWe found that cariprazine occupied D2/D3 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-HT1A receptor occupancy was considerably lower compared with D2/D3 occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei.ConclusionsWe conclude that cariprazine binds preferentially to dopamine D2/D3 rather than to serotonin 5-HT1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.

Effects of ketoconazole on the biodistribution and metabolism of [11C]loperamide and [11C]N-desmethyl-loperamide in wild-type and P-gp knockout mice

INTRODUCTION [(11)C]Loperamide and [(11)C]N-desmethyl-loperamide ([(11)C]dLop) have been proposed as radiotracers for imaging brain P-glycoprotein (P-gp) function. A major route of [(11)C]loperamide metabolism is N-demethylation to [(11)C]dLop. We aimed to test whether inhibition of CYP3A4 with ketoconazole might reduce the metabolism of [(11)C]loperamide and [(11)C]dLop in mice, and thereby improve the quality of these radiotracers. METHODS Studies were performed in wild-type and P-gp knockout (mdr-1a/b -/-) mice. During each of seven study sessions, one pair of mice, comprising one wild-type and one knockout mouse, was pretreated with ketoconazole (50 mg/kg, ip), while another such pair was left untreated. Mice were sacrificed at 30 min after injection of [(11)C]loperamide or [(11)C]dLop. Whole brain and plasma samples were measured for radioactivity and analyzed with radio-high-performance liquid chromatography. RESULTS Ketoconazole increased the plasma concentrations of [(11)C]loperamide and its main radiometabolite, [(11)C]dLop, by about twofold in both wild-type and knockout mice, whereas the most polar radiometabolite was decreased threefold. Furthermore, ketoconazole increased the brain concentrations of [(11)C]loperamide and the radiometabolite [(11)C]dLop by about twofold in knockout mice, and decreased the brain concentrations of the major and most polar radiometabolite in wild-type and knockout mice by 82% and 49%, respectively. In contrast, ketoconazole had no effect on plasma and brain distribution of administered [(11)C]dLop and its radiometabolites in either wild-type or knockout mice, except to increase the low plasma [(11)C]dLop concentration. The least polar radiometabolite of [(11)C]dLop was identified with LC-MS(n) as the N-hydroxymethyl analog of [(11)C]dLop and this also behaved as a P-gp substrate. CONCLUSION In this study, ketoconazole (50 mg/kg, ip) proved partially effective for inhibiting the N-demethylation of [(11)C]loperamide in mouse in vivo but had relatively smaller or no effect on [(11)C]dLop.