title: Quinazoline derivatives as MC-I inhibitors: evaluation of myocardial uptake using Positron Emission Tomography in rat and non-human primate.
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.
authors.affiliation: Bristol-Myers Squibb Medical Imaging, N Billerica, MA 01860, USA. ajay.purohit@bms.com
authors.forename: Ajay
authors.initials: A
authors.lastname: Purohit
authors.forename: Richard
authors.initials: R
authors.lastname: Benetti
authors.forename: Megan
authors.initials: M
authors.lastname: Hayes
authors.forename: Mary
authors.initials: M
authors.lastname: Guaraldi
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kagan
authors.forename: Padmaja
authors.initials: P
authors.lastname: Yalamanchilli
authors.forename: Fran
authors.initials: F
authors.lastname: Su
authors.forename: Michael
authors.initials: M
authors.lastname: Azure
authors.forename: Mahesh
authors.initials: M
authors.lastname: Mistry
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Simon
authors.initials: S
authors.lastname: Robinson
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Dischino
authors.forename: David
authors.initials: D
authors.lastname: Casebier
mesh_terms: 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
chemical_list: D011799:Quinazolines; D042967:Electron Transport Complex I