Synthesis and preclinical evaluation of diarylamine derivative as Tau-PET radiotracer for Alzheimer's Disease

The presence of aggregated Tau in the brain is a dominant pathological hallmark of Tauopathies, particularly in Alzheimer's disease (AD). Therefore, developing ligands that can specifically and sensitively bind to Tau aggregates is essential for diagnosing and monitoring therapeutic interventions. In this study, we further investigated the structural optimization of the diarylamine skeleton, which exhibited promising binding characteristics and biological properties. We supplementarily explored the effects of the number and position of nitrogen atoms, types of heteroatoms and aromatic moieties, and radioactive positions on affinity for Tau. Through a structure-activity relationship (SAR) analysis based on 125I-labeled diarylamine derivatives, [125I]A6 was identified as a lead compound due to its desirable binding properties and ability to penetrate the brain, making it suitable for conversion into a18F-labeled PET tracer. Satisfactorily, [18F]FA1 fulfilled critical requirements as a Tau radiotracer, demonstrating high specificity and selectivity for Tau, a clean off-target profile against Aβ plaques and monoamine oxidase B (MAO-B), and favorable in vivo brain kinetics, as confirmed by dynamic PET studies in rodents and non-human primates. [Display omitted] •Specific Tau-PET probes aid in accurate diagnosis and understanding of AD pathogenesis.•Further medicinal optimization of diarylamine skeleton was performed by 19 125I-labeled probes.•[18F]FA1 exhibited high affinity and specificity to Tau, and good in vivo properties in monkey.•Discovery of [18F]FA1 expanded the potential of diarylamine skeleton as Tau-PET imaging agents.