Synthesis and Preclinical Evaluation of 2-(4-[18F]Fluorophenyl)imidazo[1,2-h][1,7]naphthyridine ([18F]FPND-4): An Aza-Fused Tricyclic Derivative as Positron Emission Tomography Tracer for Neurofibrillary Tangle Imaging

Tau accumulation is one of the predominantneuropathological biomarkersfor in vivo diagnosis of Alzheimer's diseasedue to its high correlation with disease progression. In this study,we focused on the structure-activity relationship study ofthe substituent effect on the aza-fused tricyclic core imidazo[1,2-h][1,7]naphthyridineto screen F-18-labeled Tau tracers. Through a series ofautoradiographic studies and biological evaluations, 4-[F-18]fluorophenyl-substituted tracer [F-18]13 ([F-18]FPND-4) was identified as a promisingcandidate with high affinity to native Tau tangles (IC50 = 2.80 nM), few appreciable binding to A & beta; plaques and MAO-A/B.Validated by dynamic positron emission tomography (PET) imaging inrodents and rhesus monkey, [F-18]13 displayeddesirable brain uptake (SUV = 1.75 at 2 min), fast clearance (brain(2min/60min) = 5.9), minimal defluorination, and few off-targetbinding, which met the requirements of a Tau-specific PET radiotracer.