Development and evaluation of [¹²⁵ I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

Alzheimer'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 = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN).

Radiosynthesis 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.

[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 >1 µM concentrations.

[¹²⁵ I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.