Positron emission tomographic study of central histamine H₁-receptor occupancy in human subjects treated with epinastine, a second-generation antihistamine

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.