Monoamine oxidase binding not expected to significantly affect [(18)F]flortaucipir PET interpretation

PURPOSE: [(18)F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer’s disease biomarkers, including aggregated neurofibrillary tau (NFT) with [(18)F]flortaucipir. Due to structural similarities of flortaucipir with some monoamine oxidase A (MAO-A) inhibitors, this study aimed to evaluate flortaucipir binding to MAO-A and MAO-B and any potential impact on PET interpretation. METHODS: [(18)F]Flortaucipir autoradiography was performed on frozen human brain tissue slices, and PET imaging was conducted in rats. Dissociation constants were determined by saturation binding, association and dissociation rates were measured by kinetic binding experiments, and IC(50) values were determined by competition binding. RESULTS: Under stringent wash conditions, specific [(18)F]flortaucipir binding was observed on tau NFT-rich Alzheimer’s disease tissue and not control tissue. In vivo PET experiments in rats revealed no evidence of [(18)F]flortaucipir binding to MAO-A; pre-treatment with MAO inhibitor pargyline did not impact uptake or wash-out of [(18)F]flortaucipir. [(18)F]Flortaucipir bound with low nanomolar affinity to human MAO-A in a microsomal preparation in vitro but with a fast dissociation rate relative to MAO-A ligand fluoroethyl-harmol, consistent with no observed in vivo binding in rats of [(18)F]flortaucipir to MAO-A. Direct binding of flortaucipir to human MAO-B was not detected in a microsomal preparation. A high concentration of flortaucipir (IC(50) of 1.3 μM) was found to block binding of the MAO-B ligand safinamide to MAO-B on microsomes suggesting that, at micromolar concentrations, flortaucipir weakly binds to MAO-B in vitro. CONCLUSION: These data suggest neither MAO-A nor MAO-B binding will contribute significantly to the PET signal in cortical target areas relevant to the interpretation of [(18)F]flortaucipir. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-022-05822-9.