title: Synthesis and biological evaluation of pyridazinone analogues as potential cardiac positron emission tomography tracers.
abstract: 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.
authors.affiliation: Research and Development, Bristol-Myers Squibb Medical Imaging, 331 Treble Cove Road, North Billerica, Massachusetts 01862, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Purohit
authors.forename: Heike
authors.initials: H
authors.lastname: Radeke
authors.forename: Michael
authors.initials: M
authors.lastname: Azure
authors.forename: Kelley
authors.initials: K
authors.lastname: Hanson
authors.forename: Richard
authors.initials: R
authors.lastname: Benetti
authors.forename: Fran
authors.initials: F
authors.lastname: Su
authors.forename: Padmaja
authors.initials: P
authors.lastname: Yalamanchili
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
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: Simon
authors.initials: S
authors.lastname: Robinson
authors.forename: David
authors.initials: D
authors.lastname: Casebier
mesh_terms: D000818:Animals; D002417:Cattle; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D005260:Female; D005462:Fluorine Radioisotopes; D006321:Heart / Q000000981:diagnostic imaging*; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology; D049268:Positron-Emission Tomography; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C529805:2-tert-butyl-4-chloro-5-(4-(2-fluoroethoxymethyl)benzyloxy)-3-(2H)-pyridazinone; D005462:Fluorine Radioisotopes; D011724:Pyridazines; D019275:Radiopharmaceuticals; D042967:Electron Transport Complex I