Quinazoline derivatives as MC-I inhibitors: evaluation of myocardial uptake using Positron Emission Tomography in rat and non-human primate

Bioorg Med Chem Lett. 2007 Sep 1;17(17):4882-5. doi: 10.1016/j.bmcl.2007.06.043. Epub 2007 Jun 14.

Abstract

Several quinazoline derivatives were made as mitochondrial complex 1 inhibitors. Compound 4 showed an IC(50) of 11.3 nM and was the most potent compound of this series. The (18)F analog of 4, [(18)F] 4, was injected in the rat and showed high and rapid heart uptake, fast liver clearance, and low blood uptake. Images obtained using a microPET showed clear delineation of the myocardium in normal rats and perfusion deficit in ischemic rats. In the non-human primate, [(18)F] 4 showed rapid uptake and clearance from the myocardium and high liver uptake.

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • Electron Transport Complex I / antagonists & inhibitors*
  • Heart / drug effects
  • Inhibitory Concentration 50
  • Liver / drug effects
  • Liver / metabolism
  • Models, Chemical
  • Positron-Emission Tomography / methods*
  • Primates
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry*
  • Quinazolines / pharmacokinetics*
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Tomography, Emission-Computed, Single-Photon / methods

Substances

  • Quinazolines
  • Electron Transport Complex I