title: Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: a novel PET myocardial imaging agent.
abstract: BACKGROUND
  BMS-747158-02 is a novel fluorine 18-labeled pyridazinone derivative designed for cardiac imaging. The uptake and retention mechanisms of F-18 BMS-747158-02 in cardiac myocytes were studied in vitro, and the biodistribution of F-18 BMS-747158-02 was studied in vivo in mice.
  
  
  RESULTS
  Fluorine 19 BMS-747158-01 inhibited mitochondrial complex I (MC-I) in bovine heart submitochondrial particles with an IC(50) of 16.6 +/- 3 nmol/L that was comparable to the reference inhibitors of MC-1, rotenone, pyridaben, and deguelin (IC(50) of 18.2 +/- 6.7 nmol/L, 19.8 +/- 2.6 nmol/L, and 23.1 +/- 1.5 nmol/L, respectively). F-18 BMS-747158-02 had high uptake in monolayers of neonatal rat cardiomyocytes (10.3% +/- 0.7% of incubated drug at 60 minutes) that was inhibited by 200 nmol/L of rotenone (91% +/- 2%) and deguelin (89% +/- 3%). In contrast, an inactive pyridaben analog, P-070 (IC(50) value >4 micromol/L in MC-1 assay), did not inhibit the binding of F-18 BMS-747158-02 in cardiomyocytes. Uptake and washout kinetics for F-18 BMS-747158-02 in rat cardiomyocytes indicated that the time to half-maximal (t((1/2))) uptake was very rapid (approximately 35 seconds), and washout t((1/2)) for efflux of F-18 BMS-747158-02 was greater than 120 minutes. In vivo biodistribution studies in mice showed that F-18 BMS-747158-02 had substantial myocardial uptake (9.5% +/- 0.5% of injected dose per gram) at 60 minutes and heart-to-lung and heart-to-liver ratios of 14.1 +/- 2.5 and 8.3 +/- 0.5, respectively. Positron emission tomography imaging in the mouse allowed clear cardiac visualization and demonstrated sustained myocardial uptake through 55 minutes.
  
  
  CONCLUSIONS
  F-18 BMS-747158-02 is a novel positron emission tomography cardiac tracer targeting MC-I in cardiomyocytes with rapid uptake and slow washout. These characteristics allow fast and sustained accumulation in the heart.
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Medical Imaging, North Billerica, MA 01826, USA.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Yalamanchili
authors.forename: Eric
authors.initials: E
authors.lastname: Wexler
authors.forename: Megan
authors.initials: M
authors.lastname: Hayes
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Jody
authors.initials: J
authors.lastname: Bozek
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kagan
authors.forename: Heike S
authors.initials: HS
authors.lastname: Radeke
authors.forename: Michael
authors.initials: M
authors.lastname: Azure
authors.forename: Ajay
authors.initials: A
authors.lastname: Purohit
authors.forename: David S
authors.initials: DS
authors.lastname: Casebier
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D007089:Image Enhancement / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D032383:Myocytes, Cardiac / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D011724:Pyridazines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C525920:BMS 747158-02; D011724:Pyridazines; D019275:Radiopharmaceuticals