1. Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging.
- Author
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Gona K, Toczek J, Ye Y, Sanzida N, Golbazi A, Boodagh P, Salarian M, Jung JJ, Rajendran S, Kukreja G, Wu TL, Devel L, and Sadeghi MM
- Subjects
- Animals, Aortic Aneurysm, Abdominal enzymology, Aortic Aneurysm, Abdominal metabolism, Drug Design, Humans, Hydroxamic Acids chemical synthesis, Matrix Metalloproteinase Inhibitors chemical synthesis, Mice, Inbred C57BL, Molecular Imaging methods, Molecular Structure, Oligopeptides chemical synthesis, Organotechnetium Compounds chemical synthesis, Radiopharmaceuticals chemical synthesis, Structure-Activity Relationship, Hydroxamic Acids pharmacology, Matrix Metalloproteinase 12 metabolism, Matrix Metalloproteinase Inhibitors pharmacology, Oligopeptides pharmacology, Organotechnetium Compounds pharmacology, Radiopharmaceuticals pharmacology
- 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
99m Tc-radiotracers,99m Tc-AGA-1 and99m Tc-AGA-2, derived from AGA.99m Tc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to99m 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.- Published
- 2020
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