Quinazoline derivatives as MC-I inhibitors: evaluation of myocardial uptake using Positron Emission Tomography in rat and non-human primate.
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.
Purohit
Ajay
A
Bristol-Myers Squibb Medical Imaging, N Billerica, MA 01860, USA. ajay.purohit@bms.com
Benetti
Richard
R
Hayes
Megan
M
Guaraldi
Mary
M
Kagan
Mikhail
M
Yalamanchilli
Padmaja
P
Su
Fran
F
Azure
Michael
M
Mistry
Mahesh
M
Yu
Ming
M
Robinson
Simon
S
Dischino
Douglas D
DD
Casebier
David
D
D000818:Animals; D004353:Drug Evaluation, Preclinical; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D049268:Positron-Emission Tomography / Q000379:methods*; D011323:Primates; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D011799:Quinazolines; D042967:Electron Transport Complex I