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Abstract
As an important biomarker in Alzheimer’s disease (AD), abnormal Tau accumulation is closely associated with neurodegeneration and cognitive impairment. Positron emission tomography (PET) imaging of Tau offers a non-invasive and precise diagnostic tool. In this study, we demonstrate for the first time that electrostatic interactions significantly enhance the binding of protonated tracers to hyper-phosphorylated Tau aggregates through comprehensive investigations of radiolabeled diarylamine derivatives. This finding provides new insights into the rational design of Tau-PET tracers. Guided by this insight, we identified a promising candidate, [18F]FPPA-1, which features desirable nitrogen protonation and exhibits high affinity and selectivity for Tau aggregates, a clean off-target profile, and favorable brain kinetics in rodents, warranting further clinical evaluations in humans.
Supplementary materials
Title
The Significant Role of Nitrogen Protonation in the Rational Design of Tau-PET Tracers
Description
General information, chemical and radiochemical synthesis, immunohistochemistry, in vitro blocking study on AD brain sections, in vitro autoradiography at different pH conditions, binding properties of [125I]PPA-12 and [18F]FPPA-1, in vitro binding affinity, ex vivo biodistributions, micro-PET studies, in vitro stability studies, and NMR and MS spectra of synthesized compounds.
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