RÉSUMÉ
A series of fluorinated pyridazinone derivatives with IC50 values ranging from 8 to 4000 nM for the mitochondrial complex 1 (MC1) have been prepared. Structure-activity relationship (SAR) assessment indicated preference of the fluorine label to be incorporated on an alkyl side chain rather than directly on the pyridazinone moiety. Tissue distribution studies of a series of analogues ([18F] 22-28) in Sprague-Dawley (SD) rats identified [18F]27 as the most promising radiotracer with high uptake in cardiac tissue (3.41%ID/g; 30 min post injection) in addition to favorable heart to nontarget organ distribution ratios. MicroPET images of SD rats and nonhuman primates after [18F]27 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.
Sujet(s)
Coeur/imagerie diagnostique , Pyridazines/synthèse chimique , Radiopharmaceutiques/synthèse chimique , Animaux , Bovins , Complexe I de la chaîne respiratoire/antagonistes et inhibiteurs , Femelle , Radio-isotopes du fluor , Techniques in vitro , Macaca mulatta , Mâle , Mitochondries du myocarde/enzymologie , Tomographie par émission de positons , Pyridazines/composition chimique , Pyridazines/pharmacocinétique , Radiopharmaceutiques/composition chimique , Radiopharmaceutiques/pharmacocinétique , Rats , Rat Sprague-Dawley , Relation structure-activité , Distribution tissulaireRÉSUMÉ
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.