Radioiodinated long-chain fatty acids are attractive agents to evaluate myocardial fatty acid metabolism since these agents are concentrated in the heart muscle as analogues of substrates for energy production. Structurally-modified fatty acids that show good uptake but prolonged retention are excellent candidates for both planar and high quality single photon computerized tomagraphic (SPECT) imaging. We have found that methyl-branching is an excellent structural feature that results in the prolonged residence of redioiodinated fatty acids. Studies in experimental animals have demonstrated that under conditions of pressure overload, as encountered in experimental hypertension, regional perfusion parameters are normal while the distribution of these structurally-modified fatty acids is not uniform. This is the first demonstration of this type of phenomenon with a radioiodinated fatty acid. Evaluation of aberrations of regional fatty acid uptake in such conditions of normal regional perfusion is most effectively observed and monitored with modified fatty acids that exhibit high uptake, good heart:blood ratios and prolonged retention. It may be that fatty acid metabolism in the chronic state is necessary to preserve ventricular function. Because of the importance of optimizing the structural features of modified fatty acids to further study this phenomenon, we propose to synthesize a series of methyl-branched analoques with both monomethyl- and dimethyl-branching in various positions of the fatty acid chain and with various chain lengths and study the myocardial uptake and kinetic properties of these agents in animals. Because of the promising properties of these agents we plan to identify the best structural features, study the distribution in intracellular lipid pools and organelles, and distribute these promising new agents to collaborators for further preclinical evaluation and potential clinical evaluation.
