Use of the H 3 receptor antagonist radioligand [ 3 H]‐A‐349821 to reveal in vivo receptor occupancy of cognition enhancing H 3 receptor antagonists

Background and purpose:  The histamine H 3 receptor antagonist radioligand [ 3 H]‐A‐349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H 3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H 3 receptor occupancy to blood levels and efficacy in preclinical models. Experimental approach:  In vivo cerebral cortical H 3 receptor occupancy by [ 3 H]‐A‐349821 was determined in rats from differences in [ 3 H]‐A‐349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H 3 receptors. Comparisons were made to relate antagonist H 3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five‐trial inhibitory avoidance response in rat pups. Key results:  In adult rats, [ 3 H]‐A‐349821, 1.5 µg·kg −1 , penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [ 3 H]‐A‐349821 levels were twofold higher in the latter. With increasing [ 3 H]‐A‐349821 doses, cortical H 3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [ 3 H]‐A‐349821 doses, ABT‐239 and other H 3 receptor antagonists inhibited H 3 receptor occupancy by [ 3 H]‐A‐349821 in a dose‐dependent manner. Blood levels of the antagonists corresponding to H 3 receptor occupancy were consistent with blood levels associated with efficacy in the five‐trial inhibitory avoidance response. Conclusions and implications:  When employed as an occupancy radiotracer, [ 3 H]‐A‐349821 provided valid measurements of in vivo H 3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H 3 receptor antagonists.