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发现了格林{1-8) 类似物,提高了PET成像的稳定性和功能活性

Marina D Childs¹, Arundhasa Chandrabalan², Derian Hodgson¹

¹Department of Chemistry, University of Western Ontario, 1151 Richmond Street, London, Ontario, N6A 3K7, Canada.

ACS pharmacology & translational science

|July 20, 2023

概括

研究人员通过修改其序列,改善了用于PET成像的 ghrelin 模拟物的代谢稳定性. 这种新型连接体对生长激素分泌受体 (GHSR) 保持高度亲和力,并显示出潜在的体内应用的稳定性.

科学领域:

药用化学医学化学
放射性药物化学放射性药物化学
分子药理学分子药理学

背景情况:

格雷林类似物[Inp1,Dpr3(6-FN),1Nal4,Thr8]格雷林(1-8) 胺对生长激素分泌受体1a (GHSR) 具有很高的亲和力.
初步的体内研究显示药物动力学特性不佳,包括快速清除和组织积累,引发了对其代谢稳定性的担忧.
了解和改善格林类型的代谢稳定性对于开发有效的PET成像剂至关重要.

研究的目的:

在生物系统中研究ghrelin类似物1的蛋白质溶解稳定性.
为了结构性地修改来提高代谢稳定性而不会损害GHSR结合亲和力.
为了评估新型格林素{1-8) 类似物的功能活性.

主要方法:

在体外稳定性测试中使用人体血清和肝脏S9分数来确定代谢负担.
合成和评估一个重点图书馆的格林素{1-8) 类似物.
结构-活动-稳定性关系研究以指导模拟设计.
在体外功能测试以评估G蛋白和β-arrestin合.

主要成果:

在格林类同类1中,在Leu5和Ser6之间发现了代谢软点.
用l-2,3-diaminopropionic acid替换Ser6产生了一种具有显著改善体外稳定性的新型模拟物.
这种新型类似物保持了亚纳米GHSR亲和力,并显示出强大的G蛋白和β-arrestin合.
该研究确定了L-立体化学在稳定性第5位的关键作用.

结论:

这项研究成功地提高了基于ghrelin的PET成像探针的代谢稳定性.
开发了一种新的ghrelin (((1-8) 模拟物,其稳定性得到改善,并保留了对GHSR的高度亲和力.
这些发现证明了平衡候选PET成像剂的亲和力,稳定性和功效的可行性.

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