Kinetic modeling of hyperpolarized 13C1-pyruvate metabolism in normal rats and TRAMP mice

Abstract

Purpose To investigate metabolic exchange between 13C1-pyruvate, 13C1-lactate, and 13C1-alanine in preclinical model systems using kinetic modeling of dynamic hyperpolarized 13C spectroscopic data and to examine the relationship between fitted parameters and dose–response. Materials and methods Dynamic 13C spectroscopy data were acquired in normal rats, wild type mice, and mice with transgenic prostate tumors (TRAMP) either within a single slice or using a one-dimensional echo-planar spectroscopic imaging (1D-EPSI) encoding technique. Rate constants were estimated by fitting a set of exponential equations to the dynamic data. Variations in fitted parameters were used to determine model robustness in 15 mm slices centered on normal rat kidneys. Parameter values were used to investigate differences in metabolism between and within TRAMP and wild type mice. Results The kinetic model was shown here to be robust when fitting data from a rat given similar doses. In normal rats, Michaelis–Menten kinetics were able to describe the dose–response of the fitted exchange rate constants with a 13.65% and 16.75% scaled fitting error (SFE) for kpyr→lac and kpyr→ala, respectively. In TRAMP mice, kpyr→lac increased an average of 94% after up to 23 days of disease progression, whether the mice were untreated or treated with casodex. Parameters estimated from dynamic 13C 1D-EPSI data were able to differentiate anatomical structures within both wild type and TRAMP mice. Conclusions The metabolic parameters estimated using this approach may be useful for in vivo monitoring of tumor progression and treatment efficacy, as well as to distinguish between various tissues based on metabolic activity.

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

“…31 Nonetheless, the validity of hyperpolarized 13 C exchange rates to investigate metabolic changes in pathology has been demonstrated in cardiac diseases 28,32 and cancer. 33 Biomarkers of Gluconeogenesis: k pyr->asp , k pyr->mal . Although both malate and aspartate signals were increased in the fatty liver, k pyr->asp , rather than k pyr->mal (data not shown), correlated linearly to PC activity.…”

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

“…MCT activity is known to play a significant role in the observed pyruvate-lactate exchange in vivo (35,36) and we have shown previously in EL4 cells in vitro that the rate of label exchange between injected pyruvate and endogenous lactate is affected by both MCT and lactate dehydrogenase activity (26). In a spin echo experiment with injected hyperpolarized [1-13 C]pyruvate, the increase in the pyruvate echo/FID ratio was also decreased by 4-CIN, again suggesting that at least part of the increase in the ratio is due to cell uptake.…”

Measurement of Arterial Input Function in Hyperpolarized 13C Studies

“…The signal of [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvate at 172 ppm or [1-13 C] pyruvate hydrate at 180 ppm was integrated using Varian software. The T 1 relaxation times were determined by fitting the time courses of signal intensity starting at the maximum value using a two-parameter, mono-exponential decay function in Origin 8.6 (OriginLab Corporation, Northampton, MA).…”

“…This approach is very sensitive to the timing of the data acquisition, the injection of pyruvate, and the arrival of pyruvate to the tissue of interest. An alternative approach is to measure the lactate and pyruvate signals over time and fit these to a kinetic model [5][6][7][8][9]. However, these kinetic models are generally not measuring metabolic rates through specific enzymes or pathways.…”