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

Abstract

A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ_1–42 aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for ¹⁸F 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 (<i>n</i> = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [¹⁸F]-5-(5-(2-fluoroethoxy)­benzo­[<i>d</i>]­oxazol-2-yl)-<i>N</i>-methylpyridin-2-amine ([¹⁸F]<b>32</b>) (<i>K</i>_i = 8.0 ± 3.2 nM) displayed a brain_2min/brain_60min ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [¹⁸F]<b>32</b> to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [¹⁸F]<b>32</b> is a promising Aβ imaging agent for PET and merits further evaluation in human subjects