Development and Preclinical Evaluation of PET Radiotracers Targeting Adenosine A₁ Receptors.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00249

Abolghasem Gus Bakhoda, Torben D Pearson, Zhan-Guo Gao, Kelly A O'Conor, Seth M Eisenberg, Andrew C Kelleher, Yeona Kang, Jeih-San Liow, Jun Yong Choi, Woochan Kim, Jinpyo Seo, Michael L Freaney, Kenneth A Jacobson, Nora D Volkow, Sung Won Kim

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引用次数: 0

Abstract

Several adenosine A₁ receptor (A₁R) radiotracers for positron emission tomography (PET) have been developed to study their neuromodulatory functions and role in brain disorders. While two xanthine-based radiotracers ([¹¹C]-MPDX and [¹⁸F]-CPFPX) have been used in humans, we aimed to improve the metabolic stability and specific binding. Guided by structure-activity relationship (SAR) studies, 10 derivatives were synthesized with binding affinities up to 0.12 nM. Three subnanomolar candidates (3, 8, 9) were radiolabeled with C-11 (t _1/2 = 20.4 min) for evaluation using in vivo PET imaging and ex vivo rodent brain biodistribution. Although [¹¹C]8 demonstrated a higher blood-brain barrier (BBB) permeability, negligible in vivo specific binding was observed. Ex vivo studies indicated that all three compounds are substrates for brain efflux pumps. Despite optimized affinity, BBB permeability and in vivo binding specificity remain challenges. These findings inform development of nonxanthine A₁R radiotracers and highly potent CNS A₁R drugs.

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靶向腺苷A1受体的PET示踪剂的开发和临床前评价。

几种用于正电子发射断层扫描（PET）的腺苷A1受体（A1R）放射性示踪剂已经被开发出来，以研究它们的神经调节功能及其在脑部疾病中的作用。虽然已有两种基于黄嘌呤的放射性示踪剂（[11C]-MPDX和[18F]-CPFPX）用于人体，但我们的目的是提高代谢稳定性和特异性结合。在构效关系（SAR）研究的指导下，合成了10个结合亲和力达0.12 nM的衍生物。三个亚纳摩尔候选（3,8,9）用C-11放射标记（t 1/2 = 20.4 min），用于体内PET成像和离体啮齿动物大脑生物分布评估。虽然[11C]8显示出更高的血脑屏障（BBB）通透性，但观察到的体内特异性结合可以忽略不计。体外研究表明，这三种化合物都是脑外排泵的底物。尽管优化了亲和力，血脑屏障的通透性和体内结合特异性仍然是挑战。这些发现为非黄嘌呤A1R放射性示踪剂和高效中枢神经系统A1R药物的开发提供了信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.