Magnetization transfer measurements of exchange between hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate in a murine lymphoma

Abstract

Measurements of the conversion of hyperpolarized [1-13 C]pyruvate into lactate, in the reaction catalyzed by lactate dehydrogenase, have shown promise as a metabolic marker for the presence of disease and response to treatment. However, it is unclear whether this represents net flux of label from pyruvate to lactate or exchange of isotope between metabolites that are close to chemical equilibrium. Using saturation and inversion transfer experiments, we show that there is significant exchange of label between lactate and pyruvate in a murine lymphoma in vivo. The rate constants estimated from the magnetization transfer experiments, at specific points during the time course of label exchange, were similar to those obtained by fitting the changes in peak intensities during the entire exchange time course to a kinetic model for two-site exchange. These magnetization transfer experiments may therefore provide an alternative and more rapid way of estimating flux between pyruvate and lactate to serial measurements of pyruvate and lactate 13 C peak intensities following injection of hyperpolarized [1-13 C]pyruvate. Magn Reson Med 63:872-880,

Detection of Tumor Response to a Vascular Disrupting Agent by Hyperpolarized 13C Magnetic Resonance Spectroscopy

“…The absence of a significant change in lactate concentration between 6 and 24 hours after CA4P treatment is consistent with the notion that the hyperpolarized [1-13 C]pyruvate is labeling, by passive exchange, a preexisting lactate pool rather than there being significant net conversion of pyruvate to lactate. The evidence that we are measuring predominantly exchange, rather than (21,39). The decrease in k P at 6 hours after CA4P treatment occurred despite a 50% increase in LDH activity, which by 24 hours had declined toward pretreatment levels.…”

Spin echo measurements of the extravasation and tumor cell uptake of hyperpolarized [1‐13C]lactate and [1‐13C]pyruvate

“…Exchange of hyperpolarized 13 C label between [1-13 C]pyruvate and endogenous lactate was analyzed using a simple two-site exchange model (8), to give the first order rate constant describing flux of label between pyruvate and lactate (k P ) and the relaxation rate constant for both species (R 1 ). In experiments with [1][2][3][4][5][6][7][8][9][10][11][12][13] C]lactate, there is minimal exchange of label with the small endogenous pyruvate pool (17) and therefore R 1 for lactate was estimated directly from its apparently monoexponential signal decay.…”

“…For studies of the effect of MCT inhibition on the echo/FID ratio following injection of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]lactate (n ¼ 25), data were acquired using a surface coil and the S180 pulse sequence with an echo time of 310 ms. These acquisition conditions match those used in the heteronuclear spin-echo experiment described in our previous study with L-[U-2 H,1-…”

“…The most widely used 13 C-labeled substrate to date has been pyruvate, which has found applications in imaging metabolism, particularly in tumors (4,5) and heart (6). In tumors, following injection of hyperpolarized [1- 13 C]pyruvate, a high level of lactate labeling was observed (7), which was subsequently shown to be due to exchange of the hyperpolarized 13 C label between pyruvate and the large endogenous lactate pool that results from the high glycolytic rate that characterizes tumors (8,9). This lactate labeling was decreased in tumors that showed a positive response to treatment (4,5,8).…”

“…Previously this has only been achieved by measuring the FID and echo signals separately after two sequential injections of pyruvate (14,15). In a recent study, in which we measured exchange of deuterium label between the C2 position of hyperpolarized L-[U-2 H, [1][2][3][4][5][6][7][8][9][10][11][12][13] C]lactate and the C2 protons in endogenous lactate, where the exchange was monitored indirectly by phase modulation of the spin-coupled hyperpolarized 13 C label in a heteronuclear spin echo experiment (TE ¼ 310 ms) (17), we observed an increase in the echo signal relative to the FID signal. The increase in this echo/FID ratio can be explained by suppression of the lactate signal in the vascular space due to flow, with the increase in the ratio reflecting redistribution of lactate between the vascular and extravascular spaces.…”