Histamine H1-receptor occupancy in the human brain was measured in healthy young volunteers by positron emission tomography (PET) using [11C]doxepin. d-Chlorpheniramine, a selective and classical antihistamine, occupied 76.8 +/- 4.2% of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg. Epinastine, a non-sedative antihistamine, occupied 13.2 +/- 18.5% of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 20 mg. There was significant correlation between H1 receptor occupancy by epinastine and its plasma concentration in each subject. PET data on the human brain were essentially compatible with those on H1-receptor occupancy in the guinea pig brain as determined by an in vivo binding technique, although for the same H1-receptor occupancy, the dose was less in humans than in guinea pigs. Our PET studies demonstrated that receptor occupancy by a second-generation H1 antagonist, epinastine, was less than 20% of the total H1 receptors, and that the low receptor occupancy was closely related to the low incidence of central side effects.