Novel Matrix Metalloproteinase 12 Selective Radiotracers for Vascular Molecular Imaging

J Med Chem. 2019 Nov 14;62(21):9743-9752. doi: 10.1021/acs.jmedchem.9b01186. Epub 2019 Oct 25.

Abstract

Matrix metalloproteinase-12 (MMP-12) is highly upregulated in several inflammatory diseases, including abdominal aortic aneurysm (AAA). Here we report four novel 99mTc-labeled radiotracers derived from a highly selective competitive MMP-12 inhibitor. These tracers in their 99gTc version were assessed in vitro on a set of human metalloproteases and displayed high affinity and selectivity toward MMP-12. Their radiolabeling with 99mTc was shown to be efficient and stable in both buffer and mouse blood. The tracers showed major differences in their biodistribution and blood clearance. On the basis of its in vivo performance, [99mTc]-1 was selected for evaluation in murine AAA, where MMP-12 gene expression is upregulated. Autoradiography of aortae at 2 h postinjection revealed high uptake of [99mTc]-1 in AAA relative to adjacent aorta. Tracer uptake specificity was demonstrated through in vivo competition. This study paves the way for further evaluation of [99mTc]-1 for imaging AAA and other MMP-12-associated diseases.

Publication types

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

MeSH terms

  • Animals
  • Aorta / diagnostic imaging*
  • Aortic Aneurysm, Abdominal / diagnostic imaging
  • Humans
  • Male
  • Matrix Metalloproteinase 12 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacokinetics
  • Mice
  • Mice, Inbred C57BL
  • Molecular Imaging / methods*
  • Organotechnetium Compounds / chemistry*
  • Radioactive Tracers
  • Radiochemistry
  • Tissue Distribution
  • Up-Regulation

Substances

  • Matrix Metalloproteinase Inhibitors
  • Organotechnetium Compounds
  • Radioactive Tracers
  • Matrix Metalloproteinase 12