Synthesis and Evaluation of Novel <sup>18</sup>F Labeled 2‑Pyridinylbenzoxazole and 2‑Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β‑Amyloid Plaques
2012-11-08T00:00:00Z (GMT) by
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<sub>1–42</sub> aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for <sup>18</sup>F 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, [<sup>18</sup>F]-5-(5-(2-fluoroethoxy)benzo[<i>d</i>]oxazol-2-yl)-<i>N</i>-methylpyridin-2-amine ([<sup>18</sup>F]<b>32</b>) (<i>K</i><sub>i</sub> = 8.0 ± 3.2 nM) displayed a brain<sub>2min</sub>/brain<sub>60min</sub> ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [<sup>18</sup>F]<b>32</b> to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [<sup>18</sup>F]<b>32</b> is a promising Aβ imaging agent for PET and merits further evaluation in human subjects.