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

Abstract

Tau accumulation is one of the predominant neuropathological biomarkers for in vivo 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 18F-labeled Tau tracers. Through a series of autoradiographic studies and biological evaluations, 4-[18F]fluorophenyl-substituted tracer [18F]13 ([18F]FPND-4) was identified as a promising candidate with high affinity to native Tau tangles (IC50 = 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, [18F]13 displayed desirable brain uptake (SUV = 1.75 at 2 min), fast clearance (brain2min/60min = 5.9), minimal defluorination, and few off-target binding, which met the requirements of a Tau-specific PET radiotracer.

Discovery and Evaluation of Imidazo[2,1-b][1,3,4]thiadiazole Derivatives as New Candidates for α-Synuclein PET Imaging

“…In vivo dynamic micro PET/CT imaging studies were conducted and analyzed using our previously reported method . In this experiment, a solution of [ 18 F] FITA-1 (17.2–17.5 MBq/kg, n = 2) or [ 18 F] FITA-2 (17.2–20.9 MBq/kg, n = 3) in % 10 EtOH saline solution was injected via the tail vein of normal mice.…”

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…[ 18 F] 8 had high affinity to native tau tangles and little appreciable binding to Aβ plaques and MAO-A/B. PET imaging in rodents and rhesus monkeys using [ 18 F] 8 displayed desirable brain uptake, fast clearance, minimal defluorination, and low off-target binding …”

Highlight selection of radiochemistry and radiopharmacy developments by editorial board

“…5 ). The new imidazole naphthyridine scaffold was discovered and evaluated by the same group in their previous work (Liu et al 2023b ). The absence of off-target binding of FPND-4 to Aβ and MAO-A/B was validated.…”