A new class of highly potent matrix metalloproteinase inhibitors based on triazole-substituted hydroxamates: (radio)synthesis and in vitro and first in vivo evaluation

J Med Chem. 2012 May 24;55(10):4714-27. doi: 10.1021/jm300199g. Epub 2012 May 16.

Abstract

In vivo imaging of MMPs is of great (pre)clinical interest and can potentially be realized with modern three-dimensional and noninvasive in vivo molecular imaging techniques such as positron emission tomography (PET). Consequently, MMP inhibitors (MMPIs) radiolabeled with positron emitting nuclides (e.g., (18)F) represent a suitable tool for the visualization of activated MMPs with PET. On the basis of our previous work and results regarding radiolabeled and unlabeled derivatives of the nonselective MMPIs, we discovered a new class of fluorinated MMPIs with a triazole-substituted hydroxamate substructure. These novel MMPIs are characterized by an increased hydrophilicity compared with the lead structures and excellent MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13 (IC(50) = 0.006-107 nM). Therefore, one promising fluorinated triazole-substituted hydroxamate (30b) was selected and resynthesised as its (18)F-labeled version to yield the potential PET radioligand [(18)F]30b. The biodistribution behavior of this novel compound was investigated with small animal PET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Stability
  • Enzyme Assays
  • Fluorine Radioisotopes
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacokinetics
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics
  • Tissue Distribution
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacokinetics

Substances

  • 2-(N-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-4-methoxyphenylsulfonamido)-N-hydroxy-3-methylbutanamide
  • Fluorine Radioisotopes
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Radiopharmaceuticals
  • Sulfonamides
  • Triazoles
  • Matrix Metalloproteinases