A Novel ~(18)F Labelled Imidazo-oxazolopyridine Derivative as β-Amyloid Imaging Agent: Synthesis and Preliminary Evaluation

摘要

Visualization of β-amyloid plaques in brain is pivotal for the diagnosis of Alzheimer's disease. In the present study, we have designed, synthesized and evaluated an imidazo-oxazolopyridine derivative, 2-[2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6- yl]oxazolo[4,5-b]pyridine (FPIPOP) as a promising candidate for imaging of Aβ42 plaques using positron emission tomography (PET). Molecular docking of FPIPOP with Aβ42 fibrils predicted good affinity. The target compound was synthesized with high chemical yield and easily reproducible steps. In assays using thioflavin S as a competitive ligand, FPIPOP showed good affinity towards Aβ42 aggregates (Ki = 27.18 ± 4.7 nM). In PET experiments with normal Sprague dawley rat, high brain uptake and rapid clearance of activity was observed in cerebral cortex post i.v. injection (2.6 % ID/g for [~(18)F]FPIPOP at 1 min and 0.8 % ID/g at 60 min). [~(18)F]FPIPOP was found 76.4 % intact in brain for 60 min post injection. The ratio of radioactivity at maximal uptake to that at 60 min reached 20.5 for striatum, 26.4 for hippocampus and 33.1 for cerebellum. These results demonstrate that FPIPOP derivative has favourable in vivo brain pharmacokinetics and affinity for β-amyloid plaques; however, further optimization is required before pre-clinical evaluation of such skeletons in transgenic (Tg) mice models.