Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging

J Med Chem. 2020 Dec 10;63(23):15037-15049. doi: 10.1021/acs.jmedchem.0c01514. Epub 2020 Nov 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aortic Aneurysm, Abdominal / enzymology
  • Aortic Aneurysm, Abdominal / metabolism
  • Drug Design
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / pharmacology*
  • Matrix Metalloproteinase 12 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Mice, Inbred C57BL
  • Molecular Imaging / methods
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / pharmacology*
  • Organotechnetium Compounds / chemical synthesis
  • Organotechnetium Compounds / pharmacology*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacology*
  • Structure-Activity Relationship

Substances

  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Oligopeptides
  • Organotechnetium Compounds
  • Radiopharmaceuticals
  • MMP12 protein, human
  • Matrix Metalloproteinase 12