Synthesis and biological evaluation of pyridazinone analogues as potential cardiac positron emission tomography tracers |
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Authors: | Purohit Ajay Radeke Heike Azure Michael Hanson Kelley Benetti Richard Su Fran Yalamanchili Padmaja Yu Ming Hayes Megan Guaraldi Mary Kagan Mikhail Robinson Simon Casebier David |
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Affiliation: | Research and Development, Bristol-Myers Squibb Medical Imaging, 331 Treble Cove Road, North Billerica, Massachusetts 01862, USA. |
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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. |
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