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

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 17; pp. 4882 - 4885
• Main Authors: Purohit, Ajay, Benetti, Richard, Hayes, Megan, Guaraldi, Mary, Kagan, Mikhail, Yalamanchilli, Padmaja, Su, Fran, Azure, Michael, Mistry, Mahesh, Yu, Ming, Robinson, Simon, Dischino, Douglas D., Casebier, David
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2007; Elsevier
• Subjects: Animals; Biological and medical sciences; Contrast media. Radiopharmaceuticals; Drug Evaluation, Preclinical; Electron Transport Complex I - antagonists & inhibitors; Heart - drug effects; Inhibitory Concentration 50; Liver - drug effects; Liver - metabolism; MC-I inhibitors; Medical sciences; Models, Chemical; Myocardial perfusion; Pharmacology. Drug treatments; Positron Emission Tomography; Positron-Emission Tomography - methods; Primates; Quinazoline derivatives; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacokinetics; Rabbits; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tomography, Emission-Computed, Single-Photon - methods; Myocardial perfusion; Quinazoline derivatives; MC-I inhibitors; Positron Emission Tomography; Heart; Intravenous administration; Fluorine 18; Rat; Nitrogen heterocycle; Cardiovascular disease; Clearance; Blood; Tissue; Ischemia; Structure activity relation; Scintigraphic agent; Bicyclic compound; Primates; Aromatic compound; Chemical synthesis; NADH dehydrogenase (ubiquinone); Fluorine Isotopes; Radiolabelling; Enzyme; Rodentia; Benzene derivatives; Enzyme inhibitor; Normal; Uptake; Vertebrata; Mammalia; Animal; Distribution; Myocardium; Oxidoreductases; Pharmacokinetics; Positron emission tomography
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.06.043

Several quinazoline derivatives based on fenazaquin were synthesized as highly potent MC-I inhibitors. One of these (shown above) was radiolabeled using 18F and was shown to have rapid uptake and retention in the heart. 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 18F analog of 4, [ 18F] 4, was injected in the rat and showed high and rapid heart uptake, fast liver clearance, and low blood uptake. Images obtained using a μPET showed clear delineation of the myocardium in normal rats and perfusion deficit in ischemic rats. In the non-human primate, [ 18F] 4 showed rapid uptake and clearance from the myocardium and high liver uptake.