| Literature DB >> 33206510 |
Kiran Gona1,2, Jakub Toczek1,2, Yunpeng Ye1,2, Nowshin Sanzida1,2, Arvene Golbazi1,2, Parnaz Boodagh1,2, Mani Salarian1,2, Jae-Joon Jung1,2, Saranya Rajendran1,2, Gunjan Kukreja1,2, Terence L Wu3, Laurent Devel4, Mehran M Sadeghi1,2.
Abstract
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, and 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 selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.Entities:
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Year: 2020 PMID： 33206510 PMCID： PMC8010999 DOI： 10.1021/acs.jmedchem.0c01514
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446