MAO-B Inhibitor Deprenyl Displaces [18F]AV1451 binding on human brain tissue sections and alters uptake in Nonhuman Primate Brain

487 Objectives: Multiple groups have reported on the off-target binding of [18F]AV1451 (flortaucipir) to monoamine oxidases (MAO) in limited, in vitro experiments.1 Additionally, acute administration of the MAO-B inhibitor selegiline decreased another first generation tau tracer, [18F]THK5351, binding by 36-51% in human subjects, jeopardizing the tracer’s utility as a tau imaging agent.2 While [18F]AV1451 sees higher clinical usage than [18F]THK5351, it has not been subject to a sufficient investigation of off-target binding and its involvement in data interpretation. This work aimed to evaluate the extent of [18F]AV1451 binding to MAO-B through an enzymatic activity assay, autoradiography on post-mortem human brain tissue, and small animal brain PET imaging. Methods: [18F]AV1451 was synthesized as previously described.3 Inhibition constants were determined in an enzymatic assay in from human MAO Supersomes as previously described.4 Autoradiography was performed in the absence of ethanolic washes on postmortem substantia nigra and cerebellum tissue from AD, DLB, and age-matched control subjects. Competition with AV1451 and deprenyl was used to assess binding to nonspecific sites and MAO-B. Tau and MAO-B expression on adjacent tissue sections was determined using immunohistochemistry. Blocking studies were performed in Sprague-Dawley rats and rhesus macaques with MAO inhibitors administrated prior to injection with [18F]AV1451 (rodents: 10 mg/kg clorygline or 10 mg/kg Deprenyl; primates: 1.0 mg/kg moclobemide or 0.5 mg/kg lazabemide). Results: In vitro, AV1451 is a nonselective MAO inhibitor (MAO-A: Ki= 10 uM; MAO-B Ki= 15 uM). Competition with 500 nM deprenyl reduced [18F]AV1451 binding by ~50%; in the substantia nigra, this MAO-B challenge mirrors the nonspecific binding of [18F]AV1451. Compared to tissue from age-matched controls, MAO-B immunoreactivity was 2-3 fold higher in diseased tissue sections; tau reactivity was similarly 5-10 fold higher. Clorgyline blocking in rodents increased SUV­max in the brain by 60%, while selegiline blocking did not significantly affect the parameter. Lazabemide and moclobemide administration did not significantly affect SUVs in the rhesus macaque, though blocking altered image analysis upon normalization to the cerebellar SUV. Conclusions: AV1451 is a weak, unselective inhibitor of MAO in vitro. In autoradiography experiments, [18F]AV1451 shows high nonspecific binding in the substantia nigra and cerebellum. Displacement by deprenyl insinuates that binding to MAO-B is a major source of this nonspecific signal; increased MAO-B immunoreactivity in diseased tissue further supports this suggestion. Off-target binding to MAO-B in the cerebellum may complicate its use as a reference region for [18F]AV1451 image analysis, as demonstrated by the inconsistencies in normalized SUVs between primate scans. The limitations of using non-diseased, non-human specimens for MAO blocking studies should be considered, particularly in the case of rodents, who show a different MAO expression profile than humans. References Lemoine et al.Alzheimer’s Research & Therapy (2017) 9:96 Ng et al. Alzheimer’s Research & Therapy (2017) 9:25 Mossine et al. EJNMMI Radiopharmacy & Chemistry (2017) 2(1):7 Drake et al. ACS Chemical Neuroscience (2018) 9(12):3024-7