Open AccessHydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging
Author(s) -
Kiran Gona,
Jakub Toczek,
Yunpeng Ye,
Nowshin Sanzida,
Arvene Golbazi,
Parnaz Boodagh,
Mani Salarian,
Jaejoon Jung,
Saranya Rajendran,
Gunjan Kukreja,
Terence Wu,
Laurent Devel,
Mehran M. Sadeghi
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01514
Subject(s) - chemistry , matrix metalloproteinase , ex vivo , in vivo , matrix metalloproteinase inhibitor , abdominal aortic aneurysm , pharmacology , in vitro , biochemistry , medicine , aneurysm , microbiology and biotechnology , surgery , biology
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 99m Tc-radiotracers, 99m Tc-AGA-1 and 99m Tc-AGA-2, derived from AGA. 99m Tc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99m Tc-AGA-1. Based on this, 99m Tc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99m Tc-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.