18 F-Labeled PET Tracers Specific for Adenosine A 2A Receptor: Design, Synthesis, and Biological Evaluation

• Published in: ACS chemical neuroscience Vol. 15; no. 6; pp. 1286 - 1297
• Main Authors: Yang, Tingyu, Zheng, Wei, Cheng, Xuebo, Chen, Hualong, Jiang, Zeng, Yu, Ziyue, Zhang, Lu, Xie, Yi, Du, Lianjie, Ge, Xuan, Zhang, Jiahuai, Yuan, Leilei, Liu, Yajing, Wu, Zehui
• Format: Journal Article
• Language: English
• Published: United States 20.03.2024
• Subjects: Adenosine - metabolism; Brain - diagnostic imaging; Brain - metabolism; Molecular Docking Simulation; Positron-Emission Tomography - methods; Receptor, Adenosine A2A - metabolism; [18F]MNI-444; tracer; [18F]BIBD-399; adenosine A2A receptor; positron emission tomography
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.4c00066

By modifying the structures of targeted A R antagonists and tracers, novel compounds , , , , and BIBD-399 were designed and synthesized. In vitro inhibition experiments demonstrated that , , and BIBD-399 have high affinity for A R. and [ F]BIBD-399 were successfully synthesized. In terms of biological distribution, the brain uptake of [ F]MNI-444 exhibits greater than that of and [ F]BIBD-399. PET imaging shows that is off-target in the brain, while [ F]BIBD-399 and [ F]MNI-444 can be specifically imaged in regions with high A R expression. Differently, [ F]BIBD-399 could quickly reach equilibrium in the targeted region within 10 min after administration, while [ F]MNI-444 shows a slowly increasing trend within 2 h of administration. [ F]BIBD-399 is mainly metabolized by the liver and kidney, and there is no obvious defluorination in vivo. Additional in vitro autoradiography showed that the striatal signals of [ F]BIBD-399 and [ F]MNI-444 were inhibited by the A R antagonist SCH442416 but not by the A R antagonist DPCPX, demonstrating the high A R binding specificity of [ F]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A R. Further tMCAo imaging showed that [ F]BIBD-399 can sensitively distinguish between infarcted and noninfarcted sides, a capability not observed with [ F]MNI-444. Given its pharmacokinetic properties and the ability to identify lesion regions, [ F]BIBD-399 has potential advantages in monitoring A R changes, meriting further clinical investigation.