Imaging histamine H3 receptors with [¹⁸ F]FMH3: Test-retest and occupancy studies in the non-human primate

A positron emission tomography (PET) radioligand, [¹⁸ F]FMH3, has been developed to interrogate histamine receptor subtype 3 (H3R), where dysfunction at this site is linked with obesity, sleep abnormality, and cognitive disorders. [¹⁸ F]FMH3 was evaluated for imaging central H3R sites in non-human primates through test-retest (TRT) and dose-receptor occupancy studies with two selective H3R antagonists in order to support clinical investigations. Two adult female baboons underwent [¹⁸ F]FMH3 PET brain scans in the HR+, at repeated baseline (n = 7) and following administration of escalating doses of ABT-239 (0.003-0.1m/kg, n = 4) and ciproxifan (0.5-2.1 mg/kg, n = 7). Volume of distribution (V_T ) in brain regions was estimated using the 2-tissue compartment model. TRT variability of V_T across repeated baseline scans was reported as % coefficient of variation (COV). ABT-239 and ciproxifan occupancy at H3R was estimated using the occupancy plot, and the relationship of occupancy with dose and plasma levels was determined. In baboons, distribution of [¹⁸ F]FMH3 was high in the striatum, intermediate in cortical regions, and low in the brain stem. COV of baseline V_T was 7.0 ± 3.5%, averaged across regions and animals. Dose-dependent effects of ABT-239 and ciproxifan measured the brain. ED50 and EC50, respectively, were 0.011 mg/kg and 0.942 ng/ml for ABT-239 and 0.73 mg/kg and 208.3 ng/ml for ciproxifan. [¹⁸ F]FMH3 demonstrated high TRT reliability and can be used to measure occupancy of H3R-targeted drugs. Validation in non-human primates support [¹⁸ F]FMH3 PET studies toward clinical investigations of H3R.