Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging.
Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging.
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DOI：
10.1021/acs.jmedchem.0c01514
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发表时间：
2020-12-10
影响因子：
7.3
通讯作者：
Sadeghi MM
中科院分区：
文献类型：
--
作者：
Gona K;Toczek J;Ye Y;Sanzida N;Golbazi A;Boodagh P;Salarian M;Jung JJ;Rajendran S;Kukreja G;Wu TL;Devel L;Sadeghi MM
巨噬细胞弹性蛋白酶[基质金属蛋白酶（MMP）-12]是腹主动脉瘤（AAA）中上调最多的MMP，因此MMP-12靶向成像可预测AAA进展和破裂风险。在这里，我们报告的设计，合成和评价三种新的异羟肟酸为基础的选择性MMP-12抑制剂（CGA，CGA-1和阿加）和方法，以获得MMP-12的选择性异羟肟酸为基础的panMMP抑制剂。此外，我们还报道了两种99 mTc放射性示踪剂[99 mTc]-阿加-1和[99 mTc]-阿加-2，它们源自于阿加。与[99 mTc]-阿加-1相比，[99 mTc]-阿加-2在小鼠中显示出更快的血液清除率和更好的放射化学稳定性。在此基础上，选择[99 mTc]-阿加-2作为先导示踪剂并在小鼠AAA中进行测试。放射自显影检测到AAA中的[99 mTc]-阿加-2摄取显著高于正常主动脉区域。通过离体竞争证明了示踪剂与MMP-12的特异性结合。因此，本研究介绍了一种新的MMP-12选择性抑制剂和示踪剂家族，为进一步开发这些药物作为治疗和成像剂铺平了道路。
Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and hence MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1 & AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers [99mTc]-AGA-1 and [99mTc]-AGA-2, derived from AGA. [99mTc]-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to [99mTc]-AGA-1. Based on this, [99mTc]-AGA-2 was chosen as the lead tracer and tested in murine AAA. [99mTc]-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of MMP-12-selective inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.
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DOI：
10.1161/atvbaha.110.219147
发表时间：
2011-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johnson JL;Devel L;Czarny B;George SJ;Jackson CL;Rogakos V;Beau F;Yiotakis A;Newby AC;Dive V
通讯作者：
Dive V
DOI：
10.2967/jnumed.116.176198
发表时间：
2017-01
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Golestani R;Razavian M;Ye Y;Zhang J;Jung JJ;Toczek J;Gona K;Kim HY;Elias JA;Lee CG;Homer RJ;Sadeghi MM
通讯作者：
Sadeghi MM
影响因子：
4.8
作者：
Devel, L;Rogakos, V;Dive, V
通讯作者：
Dive, V
DOI：
10.1161/01.atv.0000218496.60097.e0
发表时间：
2006-05-01
影响因子：
8.7
作者：
Kuzuya, M;Nakamura, K;Iguchi, A
通讯作者：
Iguchi, A
影响因子：
2.7
作者：
Freskos, John N.;Asmelash, Bethel;Vu, Bich
通讯作者：
Vu, Bich