Synthesis and Preclinical Evaluation of 2-(4-[F]Fluorophenyl)imidazo[1,2-h][1,7]naphthyridine ([F]FPND-4): An Aza-Fused Tricyclic Derivative as Positron Emission Tomography Tracer for Neurofibrillary Tangle Imaging.

Tau accumulation is one of the predominant neuropathological biomarkers for diagnosis of Alzheimer's disease due to its high correlation with disease progression. In this study, we focused on the structure-activity relationship study of the substituent effect on the aza-fused tricyclic core imidazo[1,2-h][1,7]naphthyridine to screen F-labeled Tau tracers. Through a series of autoradiographic studies and biological evaluations, 4-[F]fluorophenyl-substituted tracer [F] ([F]) was identified as a promising candidate with high affinity to native Tau tangles (IC = 2.80 nM), few appreciable binding to Aβ plaques and MAO-A/B. Validated by dynamic positron emission tomography (PET) imaging in rodents and rhesus monkey, [F] displayed desirable brain uptake (SUV = 1.75 at 2 min), fast clearance (brain = 5.9), minimal defluorination, and few off-target binding, which met the requirements of a Tau-specific PET radiotracer.