YKP1358 is a novel serotonin (5-HT(2A)) and dopamine (D(2)) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D(2) receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D(2) receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [(11)C]raclopride. The D(2) receptor occupancy of striatum was measured pre-dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D(2) receptor occupancy by YKP1358 increased to 53-83% at 2 h, and then decreased afterwards, ranging from 40-64% at 5 h to 20-51% at 10 h. The YKP1358 dose-plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D(2) receptor occupancy that was well predicted by a sigmoid E(max) model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D(2) receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D(2) receptor occupancy.