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

By modifying the structures of targeted A 2A R antagonists and tracers, novel compounds 3 , 7a , 9 , 12c , and BIBD-399 were designed and synthesized. In vitro inhibition experiments demonstrated that 3 , 12c , and BIBD-399 have high affinity for A 2A R. [ 18 F]3 and [ 18 F]BIBD-399 were successfully synthesized. In terms of biological distribution, the brain uptake of [ 18 F]MNI-444 exhibits greater than that of [ 18 F]3 and [ 18 F]BIBD-399. PET imaging shows that [ 18 F]3 is off-target in the brain, while [ 18 F]BIBD-399 and [ 18 F]MNI-444 can be specifically imaged in regions with high A 2A R expression. Differently, [ 18 F]BIBD-399 could quickly reach equilibrium in the targeted region within 10 min after administration, while [ 18 F]MNI-444 shows a slowly increasing trend within 2 h of administration. [ 18 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 [ 18 F]BIBD-399 and [ 18 F]MNI-444 were inhibited by the A 2A R antagonist SCH442416 but not by the A 1 R antagonist DPCPX, demonstrating the high A 2A R binding specificity of [ 18 F]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A 2A R. Further tMCAo imaging showed that [ 18 F]BIBD-399 can sensitively distinguish between infarcted and noninfarcted sides, a capability not observed with [ 18 F]MNI-444. Given its pharmacokinetic properties and the ability to identify lesion regions, [ 18 F]BIBD-399 has potential advantages in monitoring A 2A R changes, meriting further clinical investigation.