L-3-¹¹C-lactate as a PET tracer of myocardial lactate metabolism: A feasibility study

Lactate is a key myocardial energy source. Lactate metabolism is altered in a variety of conditions, such as exercise and diabetes mellitus. However, to our knowledge, noninvasive quantitative measurements of myocardial lactate metabolism have never been performed because of the lack of an adequate radiotracer. In this study we tested L-3-¹¹C-lactate ( ¹¹C-lactate) as such a tracer. Methods: Twenty-three dogs were studied under a wide range of metabolic interventions. ¹¹C-Lactate and ¹³C-lactate were injected as boluses and PET data were acquired for 1 h. Concomitant arterial and coronary sinus (ART/CS) blood samples were collected to identify ¹³C-lactate metabolites and to measure fractional myocardial extraction/production of ¹¹C metabolite fractions (¹¹C acidic: ¹¹CO₂ and ¹¹C-lactate; ¹¹C basic: ¹¹C-labeled amino acids; and ¹¹C neutral: ¹¹C-glucose). Lactate metabolism was quantified using 2 PET approaches: monoexponential clearance analysis (oxidation only) and kinetic modeling of PET ¹¹C-myocardial curves. Results: Arterial ¹¹C acidic, neutral, and basicmetabolites were identified as primarily ¹¹C-labeled lactate + pyruvate, glucose, and alanine, respectively. Despite a significant contribution of ¹¹C-glucose (23%-45%) and ¹¹C-alanine (<11%) to total arterial ¹¹C activity, both were minimally extracted (+)/produced(-) by the heart (1.7% ± 1.0% and -0.12% ± 0.84%, respectively). Whereas extraction of ¹¹C-lactate correlated nonlinearly with that of unlabeled lactate extraction (r = 0.86, P < 0.0001), ¹¹CO ₂ production correlated linearly with extraction of unlabeled lactate (r = 0.89, P < 0.0001, slope = 1.20 ± 0.13). In studies with physiologic free fatty acids (FFA) (415 ± 216 nmol/mL), ¹¹C-lactate was highly extracted (32% ± 12%) and oxidized (26% ± 14%), and PET monoexponential clearance and kinetic modeling analyses resulted in accurate estimates of lactate oxidation and metabolism. In contrast, supraphysiologic levels of plasma FFA (4,111 ± 1,709 nmol/mL) led to poor PET estimates of lactate metabolism due to negligible lactate oxidation (1% ± 2%) and complete backdiffusion of unmetabolized ¹¹C-lactate into the vasculature (28% ± 22%). Conclusion: Under conditions of net lactate extraction, L-3-¹¹C-lactate faithfully traces myocardial metabolism of exogenous lactate. Furthermore, in physiologic substrate environments, noninvasive measurements of lactate metabolism are feasible with PET using myocardial clearance analysis (oxidation) or compartmental modeling. Thus, L-3-¹¹C-lactate should prove quite useful in widening our understanding of the role that lactate oxidation plays in the heart and other tissues and organs.