Design, Synthesis, and Evaluation of ω-Iodovinyl- and ω-Iodoalkyl-Substituted Methyl Branched Long Chain Fatty Acids

Article abstract of DOI:10.1021/jm00383a020

The synthesis of a new methyl-branched fatty acid, (E)-19-iodo-3(RS)-methyl-18-nonadecenoic acid (19), is described.Methyl branching has been introduced at the 3 position to inhibit β-oxidation and radioiodide has been attached as a trans-vinyl iodide.Preparation of 19 involved a 15-step sequence of reactions climaxing with formation of the methyl ester 18 by iododestannylation of methyl (E)-19-(tri-n-butylstannyl)-3(RS)-methyl-18-nonadecenoate (17) resulting from the reaction of n-Bu3SnH with methyl 3(RS)-methyl-18-nonadecynoate (16).Methyl branching was introduced at an early stage by Friedl-Crafts acylation of thiophene with 3(RS)-methyl-4-carbomethoxybutanoyl chloride (3) generated from 3-methylglutaric anhydride.The new agent <125I>-19, showed high myocardial uptake (5 min, 4.89percent dose/g; 30 min, 3.32percent dose/g), good heart/blood (H/B) ratios (5 min, 5.4/1; 30 min, 4.3/1), and significantly greater myocardial retention in fasted rats than the corresponding straight-chain analogue 19<125I>-iodo-18-nonadecenoic acid (5 min, 3.52percent dose/g, H/B = 4.8/1; 30 min, 1.19percent dose/g, H/B = 1.6/1).Excellent myocardial images were obtained in rats after administration of <123I>-19 and confirmed the slow myocardial washout over a 60-min period.These data suggest that 19 is a good candidate for evaluation of heart disease involving aberrations in fatty acid metabolism by use of imaging techniques such as single photon emission computerized tomography (SPECT) where redistribution or washout should be minimized.