Evaluation of lactate and alanine as metabolic biomarkers of prostate cancer using 1H HR‐MAS spectroscopy of biopsy tissues

The goal of this study was to investigate the use of lactate and alanine as metabolic biomarkers of prostate cancer using ¹H high‐resolution magic angle spinning (HR‐MAS) spectroscopy of snap‐frozen transrectal ultrasound (TRUS)‐guided prostate biopsy tissues. A long‐echo‐time rotor‐synchronized Carr‐Purcell‐Meiboom‐Gill (CPMG) sequence including an electronic reference to access in vivo concentrations (ERETIC) standard was used to determine the concentrations of lactate and alanine in 82 benign and 16 malignant biopsies (mean 26.5% ± 17.2% of core). Low concentrations of lactate (0.61 ± 0.28 mmol/kg) and alanine (0.14 ± 0.06 mmol/kg) were observed in benign prostate biopsies, and there was no significant difference between benign predominantly glandular (N = 54) and stromal (N = 28) biopsies between patients with (N = 38) and without (N = 44) a positive clinical biopsy. In biopsies containing prostate cancer there was a highly significant (P < 0.0001) increase in lactate (1.59 ± 0.61 mmol/kg) and alanine (0.26 ± 0.07 mmol/kg), and minimal overlap with lactate concentrations in benign biopsies. This study demonstrates for the first time very low concentrations of lactate and alanine in benign prostate biopsy tissues. The significant increase in the concentration of both lactate and alanine in biopsy tissue containing as little as 5% cancer could be exploited in hyperpolarized ¹³C spectroscopic imaging (SI) studies of prostate cancer patients. Magn Reson Med 60:510–516, 2008. © 2008 Wiley‐Liss, Inc.     

Hyperpolarized 13C spectroscopy and an NMR‐compatible bioreactor system for the investigation of real‐time cellular metabolism

The purpose of this study was to combine a three‐dimensional NMR‐compatible bioreactor with hyperpolarized ¹³C NMR spectroscopy in order to probe cellular metabolism in real time. JM1 (immortalized rat hepatoma) cells were cultured in a three‐dimensional NMR‐compatible fluidized bioreactor. ³¹P spectra were acquired before and after each injection of hyperpolarized [1‐¹³C] pyruvate and subsequent ¹³C spectroscopy at 11.7 T. ¹H and two‐dimensional ¹H‐¹H‐total correlation spectroscopy spectra were acquired from extracts of cells grown in uniformly labeled ¹³C‐glucose, on a 16.4 T, to determine ¹³C fractional enrichment and distribution of ¹³C label. JM1 cells were found to have a high rate of aerobic glycolysis in both two‐dimensional culture and in the bioreactor, with 85% of the ¹³C label from uniformly labeled ¹³C‐glucose being present as either lactate or alanine after 23 h. Flux measurements of pyruvate through lactate dehydrogenase and alanine aminotransferase in the bioreactor system were 12.18 ± 0.49 nmols/sec/10⁸ cells and 2.39 ± 0.30 nmols/sec/10⁸ cells, respectively, were reproducible in the same bioreactor, and were not significantly different over the course of 2 days. Although this preliminary study involved immortalized cells, this combination of technologies can be extended to the real‐time metabolic exploration of primary benign and cancerous cells and tissues prior to and after therapy. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

1H‐[13C] NMR spectroscopy of the rat brain during infusion of [2‐13C] acetate at 14.1 T

Full signal intensity ¹H‐[¹³C] NMR spectroscopy, combining a preceding ¹³C‐editing block based on an inversion BISEP (B₁‐insensitive spectral editing pulse) with a spin‐echo coherence–based localization, was developed and implemented at 14.1 T. ¹³C editing of the proposed scheme was achieved by turning on and off the ¹³C adiabatic full passage in the ¹³C‐editing block to prepare inverted and noninverted ¹³C‐coupled ¹H coherences along the longitudinal axis prior to localization. The novel ¹H‐[¹³C] NMR approach was applied in vivo under infusion of the glia‐specific substrate [2‐¹³C] acetate. Besides a ～50% improvement in sensitivity, spectral dispersion was enhanced at 14.1 T, especially for J‐coupled metabolites such as glutamate and glutamine. A more distinct spectral structure at 1.9–2.2 ppm(parts per million) was observed, e.g., glutamate C3 showed a doublet pattern in both simulated ¹H spectrum and in vivo ¹³C‐edited ¹H NMR spectra. Besides ¹³C time courses of glutamate C4 and glutamine C4, the time courses of glutamate C3 and glutamine C3 obtained by ¹H‐[¹³C] NMR spectroscopy were reported for the first time. Such capability should greatly improve the ability to study neuron‐glial metabolism using ¹H‐observed ¹³C‐edited NMR spectroscopy. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Diffusion‐weighted NMR spectroscopy allows probing of 13C labeling of glutamate inside distinct metabolic compartments in the brain

In the present work, diffusion‐weighted (DW)‐NMR spectroscopy of glutamate was performed during a ¹³C‐labeled glucose infusion in monkey brain (six experiments). It is shown that glutamate ¹³C labeling occurs significantly faster at higher diffusion weightings—slightly for glutamate in position C4, and more markedly for glutamate in position C3. This demonstrates the existence of different diffusion compartments for glutamate, associated with different metabolic rates. Metabolic modeling of ¹³C enrichment time‐courses suggests that these compartments might be gray and white matter, each having a specific oxidative metabolism rate possibly paralleled by a specific glutamate diffusion coefficient. Magn Reson Med 60:306–311, 2008. © 2008 Wiley‐Liss, Inc.     

Cerebral activation by fasting induces lactate accumulation in the hypothalamus

Carbon‐13 (¹³C) high‐resolution magic angle spinning (HR‐MAS) spectroscopy was used to investigate the neuroglial coupling mechanisms underlying appetite regulation in the brain of C57BL/6J mice metabolizing [1‐¹³C]glucose. Control fed or overnight fasted mice received [1‐¹³C]glucose (20 μmol/g intraperitoneally [i.p.]), 15 min prior to brain fixation by focused microwaves. The hypothalamic region was dissected from the rest of the brain and ¹³C HR‐MAS spectra were obtained from both biopsies. Fasting resulted in a significant increase in hypothalamic [3‐¹³C]lactate and [2‐¹³C]γ‐aminobutyric acid (GABA) relative to the remaining brain. Administration of the orexigenic peptide ghrelin (0.3 nmol/g i.p.) did not increase hypothalamic [3‐¹³C]lactate or [2‐¹³C]GABA, suggesting that ghrelin signaling is not sufficient to elicit all the metabolic consequences of hypothalamic activation by fasting. Our results indicate that the hypothalamic regulation of appetite involves, in addition to the well‐known neuropeptide signaling, increased neuroglial lactate shuttling and augmented GABA concentrations. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Metabolic imaging in the anesthetized rat brain using hyperpolarized [1‐13C] pyruvate and [1‐13C] ethyl pyruvate

Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1‐¹³C]‐ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and ¹³C spectroscopic imaging was used to compare the uptake of hyperpolarized [1‐¹³C]‐ethyl pyruvate relative to hyperpolarized [1‐¹³C]‐pyruvate into anesthetized rat brain. Hyperpolarized [1‐¹³C]‐ethyl pyruvate and [1‐¹³C]‐pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range‐finding study. Magn Reson Med 63:1137–1143, 2010. © 2010 Wiley‐Liss, Inc.     

Investigation of tumor hyperpolarized [1‐13C]‐pyruvate dynamics using time‐resolved multiband RF excitation echo‐planar MRSI

Hyperpolarized [1‐¹³C]‐pyruvate is an exciting new agent for the in vivo study of cellular metabolism and a potential cancer biomarker. The nature of the hyperpolarized signal poses unique challenges because of its short duration and the loss of magnetization with every excitation. In this study, we applied a novel and efficient time‐resolved MR spectroscopic imaging (MRSI) method to investigate in a prostate cancer model the localized temporal dynamics of the uptake of [1‐¹³C]‐pyruvate and its conversion to metabolic products, specifically [1‐¹³C]‐lactate. This hyperpolarized ¹³C method used multiband excitation pulses for efficient use of the magnetization. This study demonstrated that regions of tumor were differentially characterized from normal tissue by the lactate dynamics, where tumors showed later lactate detection and longer lactate duration that was statistically significant (P < 0.001). Compared to late‐pathologic‐stage tumors, early‐ to intermediate‐stage tumors demonstrated significantly (P < 0.01) lower lactate total signal‐to‐noise ratio (SNR), with similar temporal dynamic parameters. Hyperpolarized pyruvate dynamics provided uptake, perfusion, and vascularization information on tumors and normal tissue. Large, heterogeneous tumors demonstrated spatially variable uptake of pyruvate and metabolic conversion that was consistent with cellularity and necrosis identified by histology. The results of this study demonstrated the potential of this new hyperpolarized MR dynamic method for improved cancer detection and characterization. Magn Reson Med 63:582–591, 2010. © 2010 Wiley‐Liss, Inc.     

In vivo 13C magnetic resonance spectroscopy of human brain on a clinical 3 T scanner using [2‐13C]glucose infusion and low‐power stochastic decoupling

This study presents the detection of [2‐¹³C]glucose metabolism in the carboxylic/amide region in the human brain, and demonstrates that the cerebral metabolism of [2‐¹³C]glucose can be studied in human subjects in the presence of severe hardware constraints of widely available 3 T clinical scanners and with low‐power stochastic decoupling. In the carboxylic/amide region of human brain, the primary products of ¹³C label incorporation from [2‐¹³C]glucose into glutamate, glutamine, aspartate, γ‐aminobutyric acid, and N‐acetylaspartate were detected. Unlike the commonly used alkanyl region where lipid signals spread over a broad frequency range, the carboxylic carbon signal of lipids was found to be confined to a narrow range centered at 172.5 ppm and present no spectral interference in the absence of lipid suppression. Comparison using phantoms shows that stochastic decoupling is far superior to the commonly used WALTZ sequence at very low decoupling power at 3 T. It was found that glutamine C1 and C5 can be decoupled using stochastic decoupling at 2.2 W, although glutamine protons span a frequency range of ≈700 Hz. Detailed specific absorption rate analysis was also performed using finite difference time domain numerical simulation. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Simplified 13C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo

¹³C NMR spectroscopy is a unique tool to measure the cerebral tricarboxylic acid (TCA) cycle rate in vivo. The measurement relies on metabolic modeling of glutamate C3 and C4 enrichment time courses during a ¹³C‐glucose intravenous infusion. Usual metabolic models require the plasma glucose and ¹³C‐glucose time courses as input functions, as well as the knowledge of Michaelis‐Menten kinetics parameters governing passage through the blood‐brain barrier. It is shown in the present work that, when using an infusion protocol yielding a rapidly stable plasma glucose fractional enrichment, metabolic modeling can be simplified in such a manner that this additional information on input function and glucose transport is no longer required, significantly simplifying the measurement of cerebral TCA cycle rate in vivo. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1‐13C]pyruvate and 13C magnetic resonance spectroscopic imaging

We show here that hyperpolarized [1‐¹³C]pyruvate can be used to detect treatment response in a glioma tumor model; a tumor type where detection of response with ¹⁸fluoro‐2‐deoxyglucose, using positron emission tomography, is limited by the high background signals from normal brain tissue. ¹³C chemical shift images acquired following intravenous injection of hyperpolarized [1‐¹³C]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but comparatively low levels in surrounding brain.Labeled pyruvate was observed at high levels in blood vessels above the brain and from other major vessels elsewhere but was detected at only low levels in tumor and brain.The ratio of hyperpolarized ¹³C label in tumor lactate compared to the maximum pyruvate signal in the blood vessels was decreased from 0.38 ± 0.16 to 0.23 ± 0.13, (a reduction of 34%) by 72 h following whole brain irradiation with 15 Gy. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

Detection of radiation‐induced lung injury using hyperpolarized 13C magnetic resonance spectroscopy and imaging

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized ¹³C‐pyruvate (pyruvate) and ¹³C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (p_aO₂), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized ¹³C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013. © 2012 Wiley Periodicals, Inc.     

Unambiguous assignment of the H3S and H3R deuterations of cerebral (2‐13C) glutamate by 13C NMR at 18.8 tesla

We used high‐field ¹³C NMR (18.8 T) to assign unambiguously the isotopic shifts induced by the deuterium substitutions of the H3_proR and H3_proS hydrogens of (2‐¹³C) glutamate in extracts of the brain from deuterated animals. Monodeuterated H3R or H3S glutamate diastereoisomers were produced stereospecifically either by chemical synthesis or by coupling the reactions of isocitrate dehydrogenase and aspartate aminotransferase in deuterated medium, respectively. We show that the (3S‐²H) or (3R‐²H) deuterations induce characteristic small (Δ₂ = ?0.058 parts per million (ppm)) or large (Δ₂ = ?0.071 ppm) vicinal isotopic shifts upfield of the perprotonated (2‐¹³C) glutamate resonance (at 55.5 ppm). Isotopically shifted (2‐¹³C, 3S‐²H) or (2‐¹³C, 3R‐²H) glutamate singlets are conveniently observed by high‐field ¹³C NMR in brain extracts from deuterated rats. Since the (3S‐²H) or (3R‐²H) glutamate diastereoisomers are produced stereospecifically by the cytosolic or mitochondrial isoforms of aconitase and isocitrate dehydrogenase, our results will facilitate the ¹³C NMR investigation of these enzymatic activities and their role in subcellular glutamate trafficking. Magn Reson Med 63:1088–1091, 2010. © 2010 Wiley‐Liss, Inc.     

Selective resonance suppression 1H‐[13C] NMR spectroscopy with asymmetric adiabatic RF pulses

Despite obvious improvements in spectral resolution at high magnetic field, the detection of ¹³C labeling by ¹H‐[¹³C] NMR spectroscopy remains hampered by spectral overlap, such as in the spectral region of ¹H resonances bound to C3 of glutamate (Glu) and glutamine (Gln), and C6 of N‐acetylaspartate (NAA). The aim of this study was to develop, implement, and apply a novel ¹H‐[¹³C] NMR spectroscopic editing scheme, dubbed “selective Resonance suppression by Adiabatic Carbon Editing and Decoupling single‐voxel STimulated Echo Acquisition Mode” (RACED‐STEAM). The sequence is based on the application of two asymmetric narrow‐transition‐band adiabatic RF inversion pulses at the resonance frequency of the ¹³C coupled to the protons that need to be suppressed during the mixing time (TM) period, alternating the inversion band downfield and upfield from the ¹³C resonance on odd and even scans, respectively, thus suppressing the detection of ¹H resonances bound to ¹³C within the transition band of the inversion pulse. The results demonstrate the efficient suppression of ¹H resonances bound to C3 of Glu and Gln, and C4 of Glu, which allows the ¹H resonances bound to C6 of NAA and C4 of Gln to be revealed. The measured time course of the resolved labeling into NAA C6 with the new scheme was consistent with the slow turnover of NAA. Magn Reson Med 61:260–266, 2009. © 2009 Wiley‐Liss, Inc.     

Fast dynamic 3D MR spectroscopic imaging with compressed sensing and multiband excitation pulses for hyperpolarized 13C studies

Hyperpolarized ¹³C MR spectroscopic imaging can detect not only the uptake of the pre‐polarized molecule but also its metabolic products in vivo, thus providing a powerful new method to study cellular metabolism. Imaging the dynamic perfusion and conversion of these metabolites provides additional tissue information but requires methods for efficient hyperpolarization usage and rapid acquisitions. In this work, we have developed a time‐resolved 3D MR spectroscopic imaging method for acquiring hyperpolarized ¹³C data by combining compressed sensing methods for acceleration and multiband excitation pulses to efficiently use the magnetization. This method achieved a 2 sec temporal resolution with full volumetric coverage of a mouse, and metabolites were observed for up to 60 sec following injection of hyperpolarized [1‐¹³C]‐pyruvate. The compressed sensing acquisition used random phase encode gradient blips to create a novel random undersampling pattern tailored to dynamic MR spectroscopic imaging with sampling incoherency in four (time, frequency, and two spatial) dimensions. The reconstruction was also tailored to dynamic MR spectroscopic imaging by applying a temporal wavelet sparsifying transform to exploit the inherent temporal sparsity. Customized multiband excitation pulses were designed with a lower flip angle for the [1‐¹³C]‐pyruvate substrate given its higher concentration than its metabolic products ([1‐¹³C]‐lactate and [1‐¹³C]‐alanine), thus using less hyperpolarization per excitation. This approach has enabled the monitoring of perfusion and uptake of the pyruvate, and the conversion dynamics to lactate and alanine throughout a volume with high spatial and temporal resolution. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

13C MR spectroscopy measurements of glutaminase activity in human hepatocellular carcinoma cells using hyperpolarized 13C‐labeled glutamine

Dynamic nuclear polarization (DNP) is an emerging technique for increasing the sensitivity of ¹³C MR spectroscopy (MRS). [5‐¹³C₁]Glutamine was hyperpolarized using this technique by up to 5%, representing a 6000‐fold increase in sensitivity. The conversion of hyperpolarized glutamine to glutamate by mitochondrial glutaminase was demonstrated using ¹³C‐MRS measurements in cultured human hepatoma cells (HepG2). These results represent the first step in developing an imaging technique for detecting glutamine metabolism in vivo. Furthermore, since glutamine utilization has been correlated with cell proliferation, the study suggests a new technique for detecting changes in tumor cell proliferation. Magn Reson Med 60:253–257, 2008. © 2008 Wiley‐Liss, Inc.     

Dynamic and high‐resolution metabolic imaging of hyperpolarized [1‐13C]‐pyruvate in the rat brain using a high‐performance gradient insert

Fast chemical shift imaging (CSI) techniques are advantageous in metabolic imaging of hyperpolarized compounds due to the limited duration of the signal amplification. At the same time, reducing the acquisition time in hyperpolarized imaging does not necessarily lead to the conventional penalty in signal‐to‐noise ratio that occurs in imaging at thermal equilibrium polarization levels. Here a high‐performance gradient insert was used in combination with undersampled spiral CSI to increase either the imaging speed or the spatial resolution of hyperpolarized ¹³C metabolic imaging on a clinical 3T MR scanner. Both a single‐shot sequence with a total acquisition time of 125 ms and a three‐shot sequence with a nominal in‐plane resolution of 1.5 mm were implemented. The k‐space trajectories were measured and then used during image reconstruction. The technique was applied to metabolic imaging of the rat brain in vivo after the injection of hyperpolarized [1‐¹³C]‐pyruvate. Dynamic imaging afforded the measurement of region‐of‐interest‐specific time courses of pyruvate and its metabolic products, while imaging at high spatial resolution was used to better characterize the spatial distribution of the metabolite signals. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

Imaging of blood flow using hyperpolarized [(13)C]urea in preclinical cancer models

Purpose:

To demonstrate dynamic imaging of a diffusible perfusion tracer, hyperpolarized [¹³C]urea, for regional measurement of blood flow in preclinical cancer models.

Materials and Methods:

A pulse sequence using balanced steady state free precession (bSSFP) was developed, with progressively increasing flip angles for efficient sampling of the hyperpolarized magnetization. This allowed temporal and volumetric imaging of the [¹³C]urea signal. Regional signal dynamics were quantified for kidneys and liver, and estimates of relative blood flows were derived from the data. Detailed perfusion simulations were performed to validate the methodology.

Results:

Significant differences were observed in the signal patterns between normal and cancerous murine hepatic tissues. In particular, a 19% reduction in mean blood flow was observed in tumors, with 26% elevation in the tumor rim. The blood flow maps were also compared with metabolic imaging results with hyperpolarized [1‐¹³C]pyruvate.

Conclusion:

Regional assessment of perfusion is possible by imaging of hyperpolarized [¹³C]urea, which is significant for the imaging of cancer. J. Magn. Reson. Imaging 2011;33:692–697. © 2011 Wiley‐Liss, Inc.     

Application of subsecond spiral chemical shift imaging to real‐time multislice metabolic imaging of the rat in vivo after injection of hyperpolarized 13C1‐pyruvate

Dynamic nuclear polarization can create hyperpolarized compounds with MR signal‐to‐noise ratio enhancements on the order of 10,000‐fold. Both exogenous and normally occurring endogenous compounds can be polarized, and their initial concentration and downstream metabolic products can be assessed using MR spectroscopy. Given the transient nature of the hyperpolarized signal enhancement, fast imaging techniques are a critical requirement for real‐time metabolic imaging. We report on the development of an ultrafast, multislice, spiral chemical shift imaging sequence, with subsecond acquisition time, achieved on a clinical MR scanner. The technique was used for dynamic metabolic imaging in rats, with measurement of time‐resolved spatial distributions of hyperpolarized ¹³C₁‐pyruvate and metabolic products ¹³C₁‐lactate and ¹³C₁‐alanine, with a temporal resolution of as fast as 1 s. Metabolic imaging revealed different signal time courses in liver from kidney. These results demonstrate the feasibility of real‐time, hyperpolarized metabolic imaging and highlight its potential in assessing organ‐specific kinetic parameters. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Comparison of [3,4‐13C2]glucose to [6,6‐2H2]glucose as a tracer for glucose turnover by nuclear magnetic resonance

A recently introduced tracer, [3,4‐¹³C₂]glucose, was compared to the widely used tracer, [6,6‐²H₂]glucose, for measurement of whole‐body glucose turnover. The rate of glucose production (GP) was measured in rats after primed infusions of [3,4‐¹³C₂]glucose, [6,6‐²H₂]glucose, or both tracers simultaneously followed by a constant infusion of tracer(s) over 90 min. Blood glucose was purified and converted into monoacetone glucose for analysis by ¹³C NMR (for [3,4‐¹³C₂]glucose) or ¹H and ²H NMR (for [6,6‐²H₂]glucose). The values of GP measured during infusion of each single tracer were not significantly different. In rats infused with both tracers simultaneously, GP was identical as reported by each tracer, 42 ± 4 μmol/kg/min. Since ²H and ¹³C enrichment in glucose is typically much less than 2% for in vivo studies, [3,4‐¹³C₂]glucose does not interfere with measurements of ¹³C or ²H enrichment patterns and therefore is valuable when multiple metabolic pathways are being evaluated simultaneously. Magn Reson Med 53:1479–1483, 2005. © 2005 Wiley‐Liss, Inc.     

Metabolite kinetics in C6 rat glioma model using magnetic resonance spectroscopic imaging of hyperpolarized [1‐13C]pyruvate

In addition to an increased lactate‐to‐pyruvate ratio, altered metabolism of a malignant glioma can be further characterized by its kinetics. Spatially resolved dynamic data of pyruvate and lactate from C6‐implanted female Sprague–Dawley rat brain were acquired using a spiral chemical shift imaging sequence after a bolus injection of a hyperpolarized [1‐¹³C]pyruvate. Apparent rate constants for the conversion of pyruvate to lactate in three different regions (glioma, normal appearing brain, and vasculature) were estimated based on a two‐site exchange model. The apparent conversion rate constant was 0.018 ± 0.004 s^?1 (mean ± standard deviation, n = 6) for glioma, 0.009 ± 0.003 s^?1 for normal brain, and 0.005 ± 0.001 s^?1 for vasculature, whereas the lactate‐to‐pyruvate ratio, the metabolic marker used to date to identify tumor regions, was 0.36 ± 0.07 (mean ± SD), 0.24 ± 0.07, and 0.12 ± 0.02 for glioma, normal brain, and vasculature, respectively. The data suggest that the apparent conversion rate better differentiate glioma from normal brain (P = 0.001, n = 6) than the lactate‐to‐pyruvate ratio (P = 0.02). Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.