Abstract
A series of fluorinated chromone analogs with IC50 values ranging from 9 to 133 nM for the mitochondrial complex 1 (MC-I) has been prepared. A structure-activity relationship (SAR) study of the most potent fluorinated chromone analog 10 demonstrated the linkage heteroatom preference of the side chain region of the molecule while maintaining potent MC-I inhibitory activity. Tissue distribution studies 30 min after [(18)F]10 administration to Sprague-Dawley (SD) rats demonstrated high uptake of the radiotracer from the blood pool into the myocardium (2.24% ID/g), kidney (1.93% ID/g), and liver (2.00% ID/g). After 2 h about 66% of the activity in the myocardium at 30 min had been retained, whereas approximately 70% had been cleared from the liver and kidney. MicroPET images of SD rats after [(18)F]10 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.
MeSH terms
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Animals
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Cattle
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Chromones / chemical synthesis*
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Chromones / chemistry
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Chromones / pharmacokinetics
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Electron Transport Complex I / antagonists & inhibitors*
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Fluorine Radioisotopes*
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Heart / diagnostic imaging*
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In Vitro Techniques
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Isotope Labeling
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Kidney / diagnostic imaging
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Kidney / metabolism
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Liver / diagnostic imaging
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Liver / metabolism
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Lung / diagnostic imaging
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Lung / metabolism
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Male
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Myocardium / metabolism
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Positron-Emission Tomography
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Radiopharmaceuticals / chemical synthesis*
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Radiopharmaceuticals / chemistry
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Radiopharmaceuticals / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Submitochondrial Particles / drug effects
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Submitochondrial Particles / enzymology
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Sulfides / chemical synthesis*
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Sulfides / chemistry
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Sulfides / pharmacokinetics
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Technetium Tc 99m Sestamibi / pharmacokinetics
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Tissue Distribution
Substances
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2-(4-(4-fluorobutyl)benzylsulfanyl)-3-methylchromen-4-one
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Chromones
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Fluorine Radioisotopes
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Radiopharmaceuticals
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Sulfides
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Technetium Tc 99m Sestamibi
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Electron Transport Complex I