Friday, March 14, 2025
3/14/2025
PROJECT SUMMARY/ABSTRACT 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 goal of this study is to design, develop and evaluate the effectiveness of novel radioiodinated tracers for binding to Tau protein in postmortem human brains of AD and non-AD Taupathies and serve as in vivo imaging agents. These novel radioligands, such as IPPI, will be suitable for in vitro studies ([125I]IPPI), for extended positron emission tomography (PET) studies ([124I]IPPI) and for single photon emission computed tomography (SPECT) studies ([123I]IPPI). The radioligands will complement and support studies of several PET NFT imaging agents, such as [18F]MK-6240, currently being carried out in AD related disorders (ADRD). Phosphorylated Tau (pTau) is a reliable marker for NFT accumulation in AD beginning in the entorhinal cortex and hippocampus, spreading to the temporal cortex and subsequently to the neocortex. Preliminary studies using [125I]IPPI in human AD frontal cortex, anterior cingulate and hippocampus show excellent binding of [125I]IPPI to Tau consistent with total Tau (tTau) immunohistochemical (IHC) staining. However, variations in the degree of [125I]IPPI binding and sensitivity to distinguish Braak stages lower than IV needs to be understood. Several pTau species are known to be present in AD. Novel radiotracers that exhibit high binding affinity and selectivity for Tau (Ki<10 nM Tau; Ki>1 M for A) and optimal lipophilicity will be evaluated in AD, cognitively normal, progressive supranuclear palsy, Pick’s disease, corticobasal degeneration and Down’s syndrome subjects. Brain regions will be studied using radioiodinated tracers including [125/124/123I]IPPI and IHC. Methods of image analysis for detailed IHC and autoradiography will be used to correlate binding. Because of the interplay between A plaques and NFT, autoradiographic images of A plaques (using [18F]flotaza and [125I]IBETA) will also be acquired. Correlation of A plaques and NFT autoradiography will be carried out in brain regions of the same subjects. The binding of radioiodinated tracers, [125/124/123I]IPPI will also be compared with [18F]MK-6240 and [18F]AV-1451. This will further demonstrate the potential translational utility of the radioiodinated ligands for human AD imaging studies. In vivo metabolic stability, brain penetration and clearance of the [124I] and [123I]radiotracers will be evaluated in rats, wild type and Tau transgenic mice using in vivo PET and SPECT, respectively. Based on the in vitro and in vivo parameters of Tau imaging, the optimal derivative will be chosen for whole-body radiation dosimetry and acute toxicity studies. An exploratory IND application will be filed with FDA for the selected imaging agent. Thus, the overall impact of this application will be the availability of novel radioiodinated Tau imaging agent for NFT imaging using SPECT and PET. Our promising preliminary work with [125I]IPPI and [125I]INFT is indicative of the likelihood of success for imaging human NFT in ADRD using these novel radioiodinated Tau imaging agents.
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