It is proposed to study the behavior of 16-fluorohexadecanoic acid (FHDA) in the isolated perfused working rat heart. The FHDA will be labelled with the positron-emitting isotope, F-18 (t 1/2 = 110 min). We have developed an efficient synthesis of F-18 FHDA from inexpensive reactor-produced F-18. Knust et al (J Nucl Med 20:1170, 1979) have reported some intact animal experiments with FHDA. Our present aim is to correlate several measures of metabolism (O2 consumption, release of C-14 CO2 from C-14 hexadecanoic acid, tension-time index) with components of the time versus radioactivity curve obtained after administration of a bolus of FHDA. This will be done in normal, ischemic and hypoxic hearts, in hearts re-oxygenated after ischemia and in hearts from animals made deficient in L-carnitine. We believe that these isolated organ studies are the most efficient way of determining if F-18 FHDA can be used in conjunction with a transaxial positron emission tomograph to measure regional oxidation rates of long-chain fatty acids in the human myocardium. This would, e.g. enable us to assess the degree of protection afforded to an individual ischemic heart by administration of L-carnitine (Thomsen et al; Am J Cardiol 43:300, 1979). F-18 FHDA has several potential advantages over fatty acids labelled with C-11 (t 1/2 = 20 min), including greater availability and a longer half-life which makes patient use easier. Beta-oxidation of FHDA yields fluoroacetate. Since we are able to prepare FHDA of very high specific radioactivity, the toxicity of fluoroacetate will not be a problem. We will perform experiments where fluoroacetate is presented to the heart in order to understand how the preparation handles this metabolic product. The levels of F-18 species (fatty acid, lipids, fluoroacetate, fluorocitrate, fluoride) will be determined in freeze-clamped hearts at various times after FHDA. This is crucial to understanding the time radioactivity curves. Previous work with C-11 hexadecanoic acid in rabbit hearts (Goldstein et al; J Nucl Med 31:342, 1980) indicated that external measurement of oxidation of fatty acid originally incorporated into lipid is possible. Because of our experience with dynamic tomography with the ECAT positron camera (Holden et al, submitted; MS in appendix), we are in a good position to extend our work to man if the results of this work are encouraging.
