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

Abstract

Purpose: To assess the blood-tissue distribution of hyperpolarized 13 C-labeled molecules in vivo. Methods: Spin-echo experiments with simultaneous acquisition of the free induction decay (FID) signal following the excitation pulse and the spin-echo signal, were used to monitor hyperpolarized [1- 13C]lactate, [1-13 C]pyruvate, and the perfusion marker, [13 C]HP001, following their intravenous injection into tumor-bearing mice. Apparent T 2 relaxation times and diffusion coefficients were also measured. Results: An increasing tumor echo/FID ratio was observed for all three molecules, which could be explained by their extravasation into the tumor interstitial space, where T 2 relaxation times were longer and diffusion coefficients smaller. Inhibition of the monocarboxylate transporter, which decreased by 40% the label exchange between pyruvate and lactate, reduced the increase in the echo/FID ratio for pyruvate and lactate, but not for HP001, demonstrating that some of the increase in the echo/FID ratio was due to cell uptake of lactate and pyruvate. The different relaxation and diffusion behavior of the intravascular and extravascular signals affected measurements of the apparent label exchange rate constants. Conclusion: Simultaneous collection of both FID and echo signals can provide information on cell uptake thus giving further insight into the kinetics of hyperpolarized 13 C label exchange. Care is needed when comparing exchange rate constants determined in spin-echo-based studies. Magn

1H NMR and hyperpolarized 13C NMR assays of pyruvate–lactate: a comparative study

“…It has been suggested that MCTs are rate limiting in T47D breast cancer cells (17); this was investigated more quantitatively in EL-4 lymphoma cells (18), where it was found that the control of the measured rate of isotope flux is shared between both MCTs and LDH. The importance of MCTs in the apparent LDH rate constants measured by hyperpolarized 13 C NMR has been highlighted recently (19). Such deregulation of metabolic characteristics and the consequential change to apparent rate constants present potential biomarkers for therapeutic targets, and both the 1 H and 13 C NMR assays are sensitive to modulations of these important factors in vitro.…”

Dual Component Analysis for In Vivo T2 * Decay of Hyperpolarized 13C Metabolites

“…2e). The decay curves were first fitted using the non-negative least squares (NNLS) method (10) and two T 2 * components were consistently observed for both [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvate and [1][2][3][4][5][6][7][8][9][10][11][12][13] C] lactate from most of the dynamic spectra. Based on this result, decay curves were fitted using a nonlinear curve fitting algorithm (11) with the following dual exponential signal model with DC bias A:…”

“…Following injection of hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvate, increased [1-13 C] lactate signal was observed by rapid exchange of 13 C labeling between pyruvate and lactate (3) due to the high glycolytic rate of tumor characteristics (4). Intravenously injected [1-13 C] pyruvate is assumed to be predominantly in the intravascular space while the lactate is presumed to be largely in the intracellular space where the label exchange in the reaction catalyzed by the enzyme lactate dehydrogenase occurs (5). And a very rapid interconversion between lactate and pyruvate in blood has also been reported (6).…”

“…3b) from the averaged tumor and control group spectra. The T 2 * values and fraction of [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvate from the average of all spectra in the fitting interval were 4.04 ± 1.67 ms (80 ± 3%) and 28.59 ± 11.55 ms (20 ± 3%) for tumor group (n = 4) and 3.19 ± 0.95 ms (85 ± 8%) and 26.45 ± 6.16 ms (15 ± 8%) for control group (n = 3). For [1- , and those of the control group were 2.65 ± 1.42 ms (78 ± 7%) and 17.80 ± 3.02 ms (22 ± 7%).…”

In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding

“…Interestingly, small but noticeable differences in signal can be observed between SPEN and CSI, especially for pyruvate. These differences could be due to the additional diffusion weighting of the SPEN sequence, which is based on a spin echo [33]. Such weighting can decrease significantly the signal from the vasculature, the suppression of which is usually desirable as it can interfere with the measurement of metabolism.…”