Design, synthesis, and evaluation of .omega.-iodovinyl- and .omega.-iodoalkyl-substituted methyl-branched long-chain fatty acids

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Abstract
The synthesis of a new methyl-branched fatty acid, (E)-19-iodo-3(RS)-methyl-18-nonadecenoic acid (19), is described. Methyl branching was introduced at the 3-position to inhibit .beta.-oxidation and radioiodide was attached as a trans-vinyl iodide. Preparation of 19 involved a 15-step sequence of reactions climaxing with formation of the methyl ester by iododestannylation of methyl (E)-19-(tri-n-butylstannyl)-3(RS)-methyl-18-nonadecenoate resulting from the reaction of n-Bu3SnH with methyl 3(RS)-methyl-18-nonadecynoate. Methyl branching was introduced at an early stage by Friedel-Crafts acylation of thiophene with 3(RS)-methyl-4-carbomethoxybutanoyl choloride generated from 3-methylglutaric anhydride. The new agent, [125I]-19, showed high myocardial uptake (5 min, 4.89% dose/g; 30 min, 3.32% dose/g), good heart/blood (H/B) ratios (5 min, 5.4/1; 30 min, 4.3/1), and signficantly greater myocardial retention in fasted rats than the corresponding straight-chain analog 19-[125I]-iodo-18-nonadecenoic acid (5 min, 3.52% dose/g, H/B = 4.8/1; 30 min, 1.19% 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. Apparently, 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.