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Increased monoamine oxidase-A (MAO-A) activity in Alzheimer’s disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aβ plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [18F]FAZIN3 for MAO-A, [18F]flotaza and [125I]IBETA for Aβ plaques, [124/125I]IPPI for tau, and [18F]FEPPA for TSPO imaging. Brain sections of the anterior cingulate (AC; gray matter GM) and corpus callosum (CC; white matter WM) from cognitively normal control (CN, n = 6) and AD (n = 6) subjects were imaged using autoradiography and immunostaining. Using competition with clorgyline and (R)-deprenyl, the binding of [18F]FAZIN3 was confirmed to be selective to MAO-A levels in the AD brain sections. Increases in MAO-A, Aβ plaque, tau, and TSPO activity were found in the AD brains compared to the control brains. The [18F]FAZIN3 ratio in AD GM versus CN GM was 2.80, suggesting a 180% increase in MAO-A activity. Using GM-to-WM ratios of AD versus CN, a >50% increase in MAO-A activity was observed (AD/CN = 1.58). Linear positive correlations of [18F]FAZIN3 with [18F]flotaza, [125I]IBETA, and [125I]IPPI were measured and suggested an increase in MAO-A activity with increases in Aβ plaques and tau activity. Our results support the finding that MAO-A activity is elevated in the anterior cingulate cortex in AD and thus may provide a new biomarker for AD in this brain region.

ObjectiveAlzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6-[125 I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline ([125 I]IPPI), for binding to Tau protein (Ki=0.75nM) in postmortem human brain (AD and cognitively normal (CN).MethodsRadiosynthesis of [125 I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK-6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [3 H]PIB for Aβ plaques and [125 I]IPPI for Tau in AD and CN brains and evaluate drug effects.Results[125 I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (-7.8, -8.1, -8.2, -7.5 Kcal/mol) at the four sites were comparable to MK-6240 (-8.7, -8.5, -8.3, -7.5 Kcal/mol). Ratio of average grey matter (GM) [125 I]IPPI in AD versus CN was found to be 7.31 (p=.07) and AD GM/ white matter (WM) = 4.35 (p=.09). Ratio of average GM/WM [125 I]IPPI in CN was 1.21. Binding of [125 I]IPPI correlated with the presence of Tau, confirmed by anti-Tau Dako A0024. Specifically bound [125 I]IPPI to Tau in AD brains was displaced by MK-6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [125 I]IPPI binding at >1µM concentrations.Conclusion[125 I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.