Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: A novel PET myocardial imaging agent
| Autor: | David S. Casebier, Mikhail Kagan, Ming Yu, Ajay Purohit, Padmaja Yalamanchili, Michael Azure, Eric Wexler, Jody Bozek, Radeke Heike S, Simon P. Robinson, Megan Hayes |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Biodistribution Metabolic Clearance Rate Pharmacology Mice chemistry.chemical_compound Myocardial perfusion imaging In vivo Animals Medicine Myocyte Myocytes Cardiac Tissue Distribution Radiology Nuclear Medicine and imaging Submitochondrial particle Cells Cultured Mice Inbred BALB C medicine.diagnostic_test business.industry Washout Rotenone Image Enhancement Pyridazines chemistry Organ Specificity Positron-Emission Tomography Cattle Radiopharmaceuticals Cardiology and Cardiovascular Medicine Nuclear medicine business Deguelin |
| Zdroj: | Journal of Nuclear Cardiology. 14:782-788 |
| ISSN: | 1071-3581 |
| Popis: | 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. Methods and Results Fluorine 19 BMS-747158-01 inhibited mitochondrial complex I (MC-I) in bovine heart submitochondrial particles with an IC50 of 16.6 ± 3 nmol/L that was comparable to the reference inhibitors of MC-1, rotenone, pyridaben, and deguelin (IC50 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 (IC50 value >4 μmol/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 (t½) uptake was very rapid (approximately 35 seconds), and washout t½ 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. |
| Databáze: | OpenAIRE |
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