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.
Masayuki FujinagaRui LuoKatsushi KumataYiding ZhangAkiko HatoriTomoteru YamasakiLin XieWakana MoriYusuke KuriharaMasanao OgawaNobuki NengakiFeng WangMing-Rong ZhangPublished in: Journal of medicinal chemistry (2017)
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(2H)-yl)-N-methyl-N-phenylacetamide (7d) exhibited high binding affinity (Ki = 13.4 nM) with the TSPO and moderate lipophilicity (log D = 1.92). [18F]7d was radiosynthesized by [18F]fluorination of the bromopyridine precursor 7h with [18F]F- in 12 ± 5% radiochemical yield (n = 6, decay-corrected). In vitro autoradiography and PET studies of ischemic rat brain revealed higher binding of [18F]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 [18F]7d showed 93% of unchanged form in the ischemic brain at 30 min after 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 visualizing not only neuroinflammation but also glioma and will translate this radiotracer to a "first-in-human" study in our facility.
Keyphrases
- pet imaging
- positron emission tomography
- computed tomography
- cerebral ischemia
- pet ct
- resting state
- white matter
- functional connectivity
- squamous cell carcinoma
- multiple sclerosis
- radiation therapy
- subarachnoid hemorrhage
- blood brain barrier
- oxidative stress
- ultrasound guided
- lipopolysaccharide induced
- dna binding
- amino acid
- transcription factor
- deep learning
- lps induced
- locally advanced
- aqueous solution