14( R , S )-[ 18 F]Fluoro-6-thia-heptadecanoic acid as a tracer of free fatty acid uptake and oxidation in myocardium and skeletal muscle

Abstract

14( R, S)-[(18)F]Fluoro-6-thia-heptadecanoic acid ([(18)F]FTHA) is a long-chain fatty acid substrate for fatty acid metabolism. [(18)F]FTHA has been used to study fatty acid metabolism in human heart and skeletal muscle. It has been suggested that the rate of radioactivity accumulation in the myocardium reflects the beta-oxidation rate of free fatty acids (FFAs). However, the net accumulation of FFAs in tissue always represents the sum of FFA oxidation and incorporation into triglycerides. The fraction of [(18)F]FTHA entering directly into mitochondria for oxidation has not been previously measured. Eight anaesthetized pigs were studied with [(18)F]FTHA and positron emission tomography (PET). Immediately after each PET experiment, tissue samples from myocardium and skeletal muscle were taken for the isolation of mitochondria and measurements of radioactivity accumulation, and for intracellular [(18)F]FTHA metabolite analysis. Fractional [(18)F]FTHA uptake rates were calculated both by graphical analysis of PET data and by measuring (18)F in the tissue samples. Fractional [(18)F]FTHA uptake rates based on the analysis of tissue samples were 0.56+/-0.17 ml g(-1) min(-1) and 0.037+/-0.007 ml g(-1) min(-1) for myocardium and skeletal muscle (mean +/- SD), respectively. The myocardial results obtained from the PET data (0.50+/-0.11 ml g(-1) min(-1)) were similar to the values obtained from the tissue samples ( r=0.94, P=0.002). We also found that 89%+/-23% (mean+/-SD, n=7) of the (18)F entered mitochondria in myocardium, as compared with only 36%+/-15% (mean+/-SD, n=7) in skeletal muscle. Intracellular [(18)F]FTHA metabolite analysis showed that a major part of [(18)F]FTHA is metabolized in the mitochondria in the heart. Our data suggest that ~89% of [(18)F]FTHA taken up by the heart enters mitochondria. This supports the hypothesis that [(18)F]FTHA traces FFA beta-oxidation in the heart. In contrast to this, only ~36% of [(18)F]FTHA accumulated in skeletal muscle appears to directly enter mitochondria; the majority is taken up by the other cell fractions, suggesting that in skeletal muscle [(18)F]FTHA traces FFA uptake but not specifically FFA beta-oxidation.

Synthesis and Preliminary Evaluation of 18-18F-Fluoro-4-Thia-Oleate as a PET Probe of Fatty Acid Oxidation

“…Previous work with 18 F-FTHA in pigs had shown the 6-thia analog to be poorly taken up into skeletal muscle mitochondria (35). Taken together with the results of the present study, the approximate distribution of 18 F-FTHA, 18 F-FTP, and 18 F-FTO to the protein-bound mitochondrial fraction of control skeletal muscle is 36%, 50%, and 80%, respectively.…”

Right ventricular metabolic adaptations to high-intensity interval and moderate-intensity continuous training in healthy middle-aged men

“…Monleon and colleagues (24) suspected that the decrease of myocardial glucose uptake could result from increase in myocardial fatty acid oxidation rate or exercise-induced bradycardia, but neither of these was confirmed by their experiments. In the present study on humans, RVFFAU remained unaltered, and, as [ 18 F]FTHA traces not only uptake, but also ␤-oxidation in the myocardium (39), it can be assumed that also RV free fatty acid oxidation rate remained unaltered. However, in the present study, RVGU was measured during euglycemic hyperinsulinemic clamp and RVFFAU without the clamp in the fasting state.…”

Organ-specific dietary fatty acid uptake in humans using positron emission tomography coupled to computed tomography

“…These studies thus suggest that 18 FTHA initial transport into cells and mitochondria is similar to that of endogenous long-chain fatty acids. We and others, however, have found relatively less 18 FTHA esterification into tissue TG associated with reciprocal increase into tissue diacylglycerols and/or phospholipids (10,32). Thus, 18 FTHA tissue nonoxidative metabolism is qualitatively but not quantitatively different from endogenous fatty acids.…”