Development of a ¹⁸F‑Labeled Radiotracer with Improved Brain Kinetics for Positron Emission Tomography Imaging of Translocator Protein (18 kDa) in Ischemic Brain and Glioma

We designed four novel acetamido­benzoxa­zolone compounds <b>7a</b>–<b>d</b> as candidates for positron emission tomography (PET) radiotracers for imaging the translocator protein (18 kDa, TSPO) in ischemic brain and glioma. Among these compounds, 2-(5-(6-fluoropyridin-3-yl)-2-oxobenzo­[<i>d</i>]­oxazol-3­(2<i>H</i>)-yl)-<i>N</i>-methyl-<i>N</i>-phenylacetamide (<b>7d</b>) exhibited high binding affinity (<i>K</i>_i = 13.4 nM) with the TSPO and moderate lipophilicity (log <i>D</i> = 1.92). [¹⁸F]<b>7d</b> was radiosynthesized by [¹⁸F]­fluorination of the bromopyridine precursor <b>7h</b> with [¹⁸F]­F^– in 12 ± 5% radiochemical yield (<i>n</i> = 6, decay-corrected). In vitro autoradiography and PET studies of ischemic rat brain revealed higher binding of [¹⁸F]<b>7d</b> with TSPO on the ipsilateral side, as compared to the contralateral side, and improved brain kinetics compared with our previously developed radiotracers. Metabolite study of [¹⁸F]<b>7d</b> showed 93% of unchanged form in the ischemic brain at 30 min after injection. Moreover, PET study with [¹⁸F]<b>7d</b> provided a clear tumor image in a glioma-bearing rat model. We demonstrated that [¹⁸F]<b>7d</b> is a useful PET radiotracer for visualizing not only neuroinflammation but also glioma and will translate this radiotracer to a “first-in-human” study in our facility