Development of a 18F-Labelled 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 of positron emission tomography (PET) radiotracers for imaging translocator protein (18 kDa, TSPO) in ischemic brain and glioma. Among these compounds, 2-(5-(6-fluoropyridin-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide (7d) exhibited high binding affinity (Ki = 13.4 nM) with TSPO and moderate lipophilicity (cLogD: 1.92). [18F]7d was radiosynthesized by [18F]fluorination of the bromopyridine precursor 7h with [18F]F- at 9 ± 3% radiochemical yield (n = 15, decay-corrected). In vitro autoradiography and PET studies for ischemic rat brains showed significantly increased binding with TSPO on the ipsilateral side compared to the contralateral side. PET with [18F]7d showed improved brain kinetics than our radiotracers developed until now. Metabolite study of [18F]7d showed 93% of unchanged form in the ischemic brain at 30 min after radiotracer injection. Moreover, PET study with [18F]7d provided a clear tumor image in a glioma-bearing rat model. We demonstrated that [18F]7d is a useful PET radiotracer for visualization of not only neuroinflammation but also glioma and will translate this radiotracer to “first-in-human” study in our facility