新型基质金属蛋白酶 12 选择性放射性示踪剂用于血管分子成像。

Novel Matrix Metalloproteinase 12 Selective Radiotracers for Vascular Molecular Imaging.

机构信息

Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center , Yale University School of Medicine , New Haven , Connecticut 06511 , United States.

Veterans Affairs Connecticut Healthcare System , West Haven , Connecticut 06516 , United States.

出版信息

J Med Chem. 2019 Nov 14;62(21):9743-9752. doi: 10.1021/acs.jmedchem.9b01186. Epub 2019 Oct 25.

Abstract

Matrix metalloproteinase-12 (MMP-12) is highly upregulated in several inflammatory diseases, including abdominal aortic aneurysm (AAA). Here we report four novel Tc-labeled radiotracers derived from a highly selective competitive MMP-12 inhibitor. These tracers in their Tc version were assessed in vitro on a set of human metalloproteases and displayed high affinity and selectivity toward MMP-12. Their radiolabeling with Tc was shown to be efficient and stable in both buffer and mouse blood. The tracers showed major differences in their biodistribution and blood clearance. On the basis of its in vivo performance, [Tc]- was selected for evaluation in murine AAA, where MMP-12 gene expression is upregulated. Autoradiography of aortae at 2 h postinjection revealed high uptake of [Tc]- in AAA relative to adjacent aorta. Tracer uptake specificity was demonstrated through in vivo competition. This study paves the way for further evaluation of [Tc]- for imaging AAA and other MMP-12-associated diseases.

摘要

基质金属蛋白酶-12(MMP-12)在几种炎症性疾病中高度上调,包括腹主动脉瘤(AAA)。在这里,我们报告了四种源自高度选择性竞争 MMP-12 抑制剂的新型 Tc 标记放射性示踪剂。这些示踪剂在其 Tc 版本中在一组人类金属蛋白酶上进行了评估,表现出对 MMP-12 的高亲和力和选择性。在缓冲液和小鼠血液中,它们的 Tc 标记均显示出高效和稳定。示踪剂在其生物分布和血液清除方面存在显着差异。基于其体内性能,[Tc]-被选择用于 MMP-12 基因表达上调的小鼠 AAA 的评估。注射后 2 小时的主动脉自动放射显影显示 [Tc]-在 AAA 中的摄取明显高于相邻的主动脉。通过体内竞争证明了示踪剂摄取的特异性。这项研究为进一步评估 [Tc]-用于成像 AAA 和其他 MMP-12 相关疾病铺平了道路。

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