Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [ 11 C]GSK189254 in anesthetized baboon

Rationale The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone) as a high-affinity histamine H 3 receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors. Objective This study measured brain histamine H 3 receptor blockade by JNJ-39220675 (1 mg/kg) in the female baboon. Methods Positron emission tomography imaging and [ 11 C]GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H 3 receptor, was used to measure histamine H 3 receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in the anesthetized baboon. Histamine H 3 receptor availability was estimated as the total distribution volume ( V T ) in brain regions. The sensitivity of [ 11 C]GSK189254 binding to injected mass and carryover effects was determined. Results JNJ-39220675 produces robust (ca. 90 %) blockade of [ 11 C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1 mg/kg), the fractional receptor occupancy was >0.9 at 90 min with a slight increase from 90 to 240 min. Similar to prior studies in humans, V T was highly sensitive to the mass of GSK189254 with ED 50 estimated to be 0.16 μg/kg. Conclusions The robust blockade of binding of [ 11 C]GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood–brain barrier and occupies the histamine H 3 receptor after oral administration at low plasma concentrations (∼1 ng/cc) supporting further drug development for alcohol addiction and other disorders. This study corroborates prior reports of the high sensitivity of [ 11 C]GSK189254 to injected mass at doses >0.1 μg/kg.