First assessment of [18F]-FMH3 in human, a selective histamine H3 receptor PET tracer

Objectives Preclinical and early clinical evaluation of histamine H3 receptor occupancy and displacement by candidate drugs in vivo aids development of potential new treatments for Alzheimer disease and sleep disorders, and provide rational dosing strategies for Phase 2 trials. The aim of this research was to validate for the first time in healthy humans [18F]FMH3, a highly specific imaging biomarker for H3.

Methods Human and non-human primate PET studies were performed following bolus injection of [18F]FMH3 to determine the kinetics of brain uptake and washout. A total of eight PET studies were performed in two nonhuman primates evaluating the regional brain uptake and washout of radioactivity and the effects of displacement with ciproxifan at different doses. Initial human studies were performed following bolus injection of 5.1 mCi of [18F]FMH3 and serial dynamic PET acquisitions were obtained over 3.5 h post injection.

Results Serial dynamic PET images demonstrated excellent brain uptake. Ciproxifan iv administration in non-human primates demonstrated a dose-dependent displacement of H3-specific activity. Initial human studies showed SUVs peaking at 2.0-2.5 in all brain regions around 15 min post injection. Lowest uptake was found in the pons, with a rank order of globus pallidus > putamen > caudate > anterior cingulate > amygdala > cortices, cerebellum > pons. BPnd (using the pons) was 1.5-2.0 in the putamen and globus pallidus. Ratios of each region to pons increased over time and were stable between H2 and 3.5 h with ratios plateauing around 2.5-3.0 for putamen and globus pallidus.

Conclusions [18F]FMH3 is a promising radiotracer for interrogation of histamine H3 in human and non-human primates