Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET):: A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine

Aims Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H-1-receptors. We Previously Studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H-1-receptor occupation by ebastine was examined in the human brain using PET. Methods Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [C-11]-doxepin, a potent H-1-receptor antagonist, were conducted near t(max) of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/K-d) for available brain H-1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H-1-receptor occupancy of drugs was calculated in several H-1-receptor rich regions. Results Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H-1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BP's after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H-1-receptor occupancies in cortex were approximately 10% by ebastine and greater than or equal to 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54%, for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. Conclusions Ebastine (10 mg orally) causes brain histamine H-1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effiect, whereas (+)-chlorpheniramine occupied about 50% of brain H-1-receptors even at a low but sedative dose of 2 mg: occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.