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

By modifying the structures of targeted A2A 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 A2A 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 A2A 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 A2A R antagonist SCH442416 but not by the A1 R antagonist DPCPX, demonstrating the high A2A R binding specificity of [18 F]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A2A 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 A2A R changes, meriting further clinical investigation.