Abstract：
By modifying the structures of targeted A2AR 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 A2AR. [18F]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 [18F]3 and [18F]BIBD-399. PET imaging shows that [18F]3 is off-target in the brain, while [18F]BIBD-399 and [18F]MNI-444 can be specifically imaged in regions with high A2AR 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 A2AR antagonist SCH442416 but not by the A1R antagonist DPCPX, demonstrating the high A2AR binding specificity of [18F]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A2AR. 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 A2AR changes, meriting further clinical investigation.
摘要：
通过修饰靶向A2AR拮抗剂和示踪剂的结构，新化合物3，7a，9、12c、设计并合成了BIBD-399。体外抑制实验表明，3，12c，和BIBD-399对A2AR具有高亲和力。成功合成了[18F]3和[18F]BIBD-399。在生物分布方面,[18F]MNI-444的脑摄取表现出大于[18F]3和[18F]BIBD-399的脑摄取。PET成像显示[18F]3在大脑中偏离目标，而[18F]BIBD-399和[18F]MNI-444可以在具有高A2AR表达的区域中特异性成像。不同的是,[18F]BIBD-399在给药后10分钟内可以在靶向区域快速达到平衡，而[18F]MNI-444在给药后2小时内显示出缓慢增加的趋势。[18F]BIBD-399主要由肝脏和肾脏代谢，体内无明显的脱氟现象。额外的体外放射自显影显示，[18F]BIBD-399和[18F]MNI-444的纹状体信号被A2AR拮抗剂SCH442416抑制，但未被A1R拮抗剂DPCPX抑制，证明[18F]BIBD-399的高A2AR结合特异性。分子对接进一步证实了MNI-444和BIBD-399对A2AR的高亲和力。进一步的tMCAo成像显示[18F]BIBD-399可以敏感地区分梗死侧和非梗死侧，[18F]MNI-444没有观察到的能力。鉴于其药代动力学特性和识别病变区域的能力，[18F]BIBD-399在监测A2AR变化方面具有潜在优势，值得进一步的临床研究。
