¹⁸F-Labeled PET Tracers Specific for Adenosine A_2A Receptor: Design, Synthesis, and Biological Evaluation

By modifying the structures of targeted A_2AR 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_2AR. [F]3 and [¹⁸F]BIBD-399 were successfully synthesized. In terms of biological distribution, the brain uptake of [¹⁸F]MNI-444 exhibits greater than that of [F]3 and [¹⁸F]BIBD-399. PET imaging shows that [F]3 is off-target in the brain, while [¹⁸F]BIBD-399 and [¹⁸F]MNI-444 can be specifically imaged in regions with high A_2AR expression. Differently, [¹⁸F]BIBD-399 could quickly reach equilibrium in the targeted region within 10 min after administration, while [¹⁸F]MNI-444 shows a slowly increasing trend within 2 h of administration. [¹⁸F]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 [¹⁸F]BIBD-399 and [¹⁸F]MNI-444 were inhibited by the A_2AR antagonist SCH442416 but not by the A₁R antagonist DPCPX, demonstrating the high A_2AR binding specificity of [¹⁸F]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A_2AR. Further tMCAo imaging showed that [¹⁸F]BIBD-399 can sensitively distinguish between infarcted and noninfarcted sides, a capability not observed with [¹⁸F]MNI-444. Given its pharmacokinetic properties and the ability to identify lesion regions, [¹⁸F]BIBD-399 has potential advantages in monitoring A_2AR changes, meriting further clinical investigation.