[I-125]INFT: Synthesis and Evaluation of a New Imaging Agent for Tau Protein in Post-Mortem Human Alzheimer's Disease Brain

Aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) is a neuropathological feature in Alzheimer's disease (AD). This study aimed to develop and evaluate the effectiveness of a novel radioiodinated tracer, 4-[I-125]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([I-125]INFT), for binding to Tau protein in postmortem human AD brain. Radiosynthesis of [I-125]INFT was carried out using electrophilic destannylation by iodine-125 and purified chromatographically. Computational modeling of INFT binding on Tau fibril was compared with IPPI. In vitro, autoradiography studies were conducted with [I-125]INFT for Tau in AD and cognitively normal (CN) brains. [I-125]INFT was produced in >95% purity. Molecular modeling of INFT revealed comparable binding energies to IPPI at site-1 of the Tau fibril with an affinity of IC50 = 7.3 x 10(-8) M. Binding of [I-125]INFT correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. The ratio of average grey matter (GM) [I-125]INFT in AD versus CN was found to be 5.9, and AD GM/white matter (WM) = 2.5. Specifically bound [I-125]INFT to Tau in AD brains was displaced by IPPI (>90%). Monoamine oxidase inhibitor deprenyl had no effect and clorgyline had little effect on [I-125]INFT binding. [I-125]INFT is a less lipophilic imaging agent for Tau in AD.

Automated summary

This study aimed to develop and evaluate a novel radioiodinated tracer, [I-125]INFT, for binding to Tau protein in postmortem human AD brain. The results showed that [I-125]INFT binding correlated with the presence of Tau and could be used as an imaging agent for AD.