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

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