¹⁸F-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. [F-18]3 and [F-18]BIBD-399 were successfully synthesized. In terms of biological distribution, the brain uptake of [F-18]MNI-444 exhibits greater than that of [F-18]3 and [F-18]BIBD-399. PET imaging shows that [F-18]3 is off-target in the brain, while [F-18]BIBD-399 and [F-18]MNI-444 can be specifically imaged in regions with high A(2A)R expression. Differently, [F-18]BIBD-399 could quickly reach equilibrium in the targeted region within 10 min after administration, while [F-18]MNI-444 shows a slowly increasing trend within 2 h of administration. [F-18]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-18]BIBD-399 and [F-18]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 [F-18]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A(2A)R. Further tMCAo imaging showed that [F-18]BIBD-399 can sensitively distinguish between infarcted and noninfarcted sides, a capability not observed with [F-18]MNI-444. Given its pharmacokinetic properties and the ability to identify lesion regions, [F-18]BIBD-399 has potential advantages in monitoring A(2A)R changes, meriting further clinical investigation.