It is proposed to continue our studies of radiolabeled long chain fatty acids as potential radiotracers for positron tomographic applications. The ultimate goal is the determination of local values of fatty acid uptake or beta oxidation rates in the human myocardium in vivo. This work is important because long chain fatty acids are the principal fuel of the myocardium and disorders of fatty acid oxidation can lead to myopathy. Also it is believed that a large component of the irreversible myocardial damage which occurs in ischemia is due to accumulation of coenzyme A thioesters of long chain fatty acids. In the previous three year grant period we have: 1) established the physical model of the isolated perfused rat heart in our laboratory and developed improved methods of administration of labeled compounds and of acquisition of tracer kinetic data; 2) developed expertise in compartmental modeling; 3) made several contributions to Fluorine-18 chemistry; and, 4) examined in detail the kinetics and metabolism of 16-fluoro- and 16-iodohexadecanoic acids. Our attention has become focussed on the rate limitation of clearance kinetics at the levels of hydrolysis of the terminal short chain acyl coenzyme A thioester and of diffusion of the terminal catabolite out of the mitochondrial matrix. We now propose to examine a range of labeled fatty acids which have been described (iodophenyl, iodovinyl, mid-chain tellura, branch chain, etc.) with respect to the hydrolysis and diffusion steps for their terminal thioesters and catabolites. Comparison of the rate constants for these processes for several fatty acids is expected to delineate molecular factors which govern diffusion and more especially hydrolysis of the short or medium chain length thioesters. Rapid hydrolysis and diffusion are necessary for radiotracers where, as with C-11 palmitate, an index of local metabolism is inferred from clearance rates. Alternatively, fatty acids whose metabolites are hydrolysed or diffuse very slowly may allow estimation of local fatty acid uptake rates with tracer kinetic models similar to those used for 2-deoxyglucose. Because of our experience with dynamic positron tomography with the ECAT II positron camera we are in an excellent position to extend our work to man if the results of this work are encouraging.
