Radiolabeled Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitors: (Radio)Syntheses and in Vitro and First in Vivo Evaluation

J Med Chem. 2017 Jan 12;60(1):307-321. doi: 10.1021/acs.jmedchem.6b01284. Epub 2016 Dec 16.

Abstract

The noninvasive imaging of MMP activity in vivo could have a high impact in basic research as well as in clinical applications. This approach can be established using radiolabeled MMP inhibitors (MMPIs) as tracers for the detection of activated MMPs by means of PET. However, the complexity of diseases associated with dysregulated MMP expression necessitates the imaging of distinct MMPs or MMP subgroups to distinguish their individual role in specific diseases. To this end, selective and potent MMP-13 inhibitors based on a N,N'-bis(benzyl)pyrimidine-4,6-dicarboxamide core have been synthesized and successfully radiolabeled with carbon-11, fluorine-18, and gallium-68. Selected radiolabeled candidates were evaluated in vitro and in vivo regarding their pharmacokinetic properties and metabolic stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • In Vitro Techniques
  • Male
  • Matrix Metalloproteinase 13 / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / pharmacology*
  • Radiopharmaceuticals / chemistry*
  • Structure-Activity Relationship

Substances

  • Protease Inhibitors
  • Radiopharmaceuticals
  • Matrix Metalloproteinase 13