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 7a – d 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[ d ]oxazol-3(2 H )-yl)- N -methyl- N -phenylacetamide ( 7d ) exhibited high binding affinity ( K i = 13.4 nM) with the TSPO and moderate lipophilicity (log D = 1.92). [ 18 F] 7d was radiosynthesized by [ 18 F]fluorination of the bromopyridine precursor 7h with [ 18 F]F – in 12 ± 5% radiochemical yield ( n = 6, decay-corrected). In vitro autoradiography and PET studies of ischemic rat brain revealed higher binding of [ 18 F] 7d 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 [ 18 F] 7d showed 93% of unchanged form in the ischemic brain at 30 min after injection. Moreover, PET study with [ 18 F] 7d provided a clear tumor image in a glioma-bearing rat model. We demonstrated that [ 18 F] 7d 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.