[¹²⁵I]IPPI for Tau Imaging: Binding Studies in Postmortem Human Alzheimer's Disease Hippocampus‐Subiculum and Evaluation of Drug Effects

Alzheimer's disease (AD) is characterized by the accumulation of tau tangles that aggregate into neurofibrillary tangles (NFT). This study aims to assess binding of [¹²⁵I]IPPI, a recently reported imaging probe for pathological, aggregated tau in AD human hippocampus (HP) postmortem brain slices, and measure effects of drugs known to bind to tau, monoamine oxidase A (MAO-A), and dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A). Quantitative [¹²⁵I]IPPI binding was compared between AD (n = 29; 13 male and 16 female) and cognitively normal (CN) (n = 32; 16 male and 16 female) subjects. Significantly, there was more [¹²⁵I]IPPI binding in AD gray matter (GM), which positively correlated with the percent of anti-tau immunostaining. GM/white matter (WM) ratios in AD were higher compared to CN subjects. Female AD (avg. GM/WM = 2.42) exhibited greater [¹²⁵I]IPPI binding compared to males (avg. GM/WM = 1.91). Binding of [¹²⁵I]IPPI increased with Braak neurofibrillary stages of the subjects, and the effects of aging were mixed, with females showing a downward trend. A positive correlation between [¹²⁵I]IPPI binding to tau and [¹⁸F]flotaza binding to amyloid beta (Aβ) suggests potential pathophysiological associations between the two AD biomarkers. MK-6240 (aggregated tau-selective) and harmine (MAO-A, DYRK1A, and tau nonselective) inhibited [¹²⁵I]IPPI binding by 88% and 69%, respectively. No effect on [¹²⁵I]IPPI binding was observed by selective DYRK1A (KuFal194) and MAO-A (clorgyline) inhibitors. Affinity of harmine for tau binding sites was quantified by inhibitor concentration (IC₅₀) = 135 ± 29 nM. This study demonstrates promise of radiolabeled IPPI as a viable and selective tau radiotracer to assist in the diagnostic imaging of AD in humans.