Synthesis and Evaluation of Novel 18F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel beta-amyloid (A beta) imaging probes for PET. They displayed binding affinities for A beta(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for F-18 labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1, displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [F-18]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([F-18]32) (K-i = 8.0 +/- 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for A beta imaging agents. Target specific binding of [F-18]32 to A beta plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [F-18]32 is a promising A beta imaging agent for PET and merits further evaluation in human subjects.