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

作者：Fujinaga, Masayuki; Luo, Rui; Kumata, Katsushi; Zhang, Yiding; Hatori, Akiko; Yamasaki, Tomoteru; Xie, Lin; Mori, Wakana; Kurihara, Yusuke; Ogawa, Masanao; Nengaki, Nobuki; Wang, Feng^*; Zhang, Ming-Rong^*

来源：Journal of Medicinal Chemistry, 2017, 60(9): 4047-4061.

DOI：10.1021/acs.jmedchem.7b00374

• PERIPHERAL BENZODIAZEPINE-RECEPTOR
• MICROGLIAL ACTIVATION
• PET RADIOLIGANDS
• TSPO EXPRESSION
• BIOLOGICAL EVALUATION
• ALZHEIMERS-DISEASE
• BREAST-CANCER
• 11195 BINDING
• LIGAND
• NEUROINFLAMMATION

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

• 出版日期2017-5-11
• 单位南京医科大学