Probing lactate secretion in tumours with hyperpolarised NMR.

Most tumours exhibit a high rate of glycolysis and predominantly produce energy by lactic acid fermentation. To maintain energy production and prevent toxicity, the lactate generated needs to be rapidly transported out of the cell. This is achieved by monocarboxylate transporters (MCTs), which therefore play an essential role in cancer metabolism and development. In vivo experiments were performed on eight male Fisher F344 rats bearing a subcutaneous mammary carcinoma after injection of hyperpolarised [1-(13) C]pyruvate. A Gd(III)DO3A complex that binds to pyruvate and its metabolites was used to efficiently destroy the extracellular magnetisation after hyperpolarised lactate had been formed. Moreover, a pulse sequence including a frequency-selective saturation pulse was designed so that the pyruvate magnetisation could be destroyed to exclude effects arising from further conversion. Given this preparation, metabolite transport out of the cell manifested as additional decay and apparent cell membrane transporter rates could thus be obtained using a reference measurement without a relaxation agent. In addition to slice-selective spectra, spatially resolved maps of apparent membrane transporter activity were acquired using a single-shot spiral gradient readout. A considerable increase in decay rate was detected for lactate, indicating rapid transport out of the cell. The alanine signal was unaltered, which corresponds to a slower efflux rate. This technique could allow for better understanding of tumour metabolism and progression, and enable treatment response measurements for MCT-targeted cancer therapies. Moreover, it provides vital insights into the signal kinetics of hyperpolarised [1-(13) C]pyruvate examinations. Copyright © 2016 John Wiley & Sons, Ltd.

Investigation of metabolic changes in STZ-induced diabetic rats with hyperpolarized [1-13C]acetate.

In the metabolism of acetate several enzymes are involved, which play an important role in free fatty acid oxidation. Fatty acid metabolism is altered in diabetes patients and therefore acetate might serve as a marker for pathological changes in the fuel selection of cells, as these changes occur in diabetes patients. Acetylcarnitine is a metabolic product of acetate, which enables its transport into the mitochondria for energy production. This study investigates whether the ratio of acetylcarnitine to acetate, measured by noninvasive hyperpolarized [1-(13)C]acetate magnetic resonance spectroscopy, could serve as a marker for myocardial, hepatic, and renal metabolic changes in rats with Streptozotocin (STZ)-induced diabetes in vivo. We demonstrate that the conversion of acetate to acetylcarnitine could be detected and quantified in all three organs of interest. More interestingly, we found that the hyperpolarized acetylcarnitine to acetate ratio was independent of blood glucose levels and prolonged hyperglycemia following diabetes induction in a type-1 diabetes model.

Comparison of acquisition schemes for hyperpolarised ¹³C imaging.

The aim of this study was to characterise and compare widely used acquisition strategies for hyperpolarised (13)C imaging. Free induction decay chemical shift imaging (FIDCSI), echo-planar spectroscopic imaging (EPSI), IDEAL spiral chemical shift imaging (ISPCSI) and spiral chemical shift imaging (SPCSI) sequences were designed for two different regimes of spatial resolution. Their characteristics were studied in simulations and in tumour-bearing rats after injection of hyperpolarised [1-(13)C]pyruvate on a clinical 3-T scanner. Two or three different sequences were used on the same rat in random order for direct comparison. The experimentally obtained lactate signal-to-noise ratio (SNR) in the tumour matched the simulations. Differences between the sequences were mainly found in the encoding efficiency, gradient demand and artefact behaviour. Although ISPCSI and SPCSI offer high encoding efficiencies, these non-Cartesian trajectories are more prone than EPSI and FIDCSI to artefacts from various sources. If the encoding efficiency is sufficient for the desired application, EPSI has been proven to be a robust choice. Otherwise, faster spiral acquisition schemes are recommended. The conclusions found in this work can be applied directly to clinical applications.

Metabolic imaging of hyperpolarized [1-(13) C]acetate and [1-(13) C]acetylcarnitine - investigation of the influence of dobutamine induced stress.

PURPOSE: The metabolism of acetate in the heart resembles fatty acid metabolism, which is altered in several diseases like ischemia, diabetes mellitus, and heart failure. A signal-to-noise ratio (SNR) optimized imaging framework for in vivo measurements of hyperpolarized [1-(13) C]acetate and its metabolic product [1-(13) C]acetylcarnitine (ALCAR) in rats at 3 Tesla (T) is presented in this work. METHODS: A spectrospatial pulse was combined with IDEAL encoding to acquire well separated metabolic maps. The influence of dobutamine induced stress onto this metabolic system was investigated in spectra and in an imaging study. RESULTS: An increase of the ALCAR to acetate ratio with dobutamine induced stress was shown in slice selective spectra containing the rat hearts and skeletal muscles. Metabolic maps of acetate and ALCAR were acquired with an acceptable SNR. Quantification of the apparent conversion rate showed stable results in the heart in a time-window of 30 s. The effect of dobutamine on the signal intensities was shown to originate mainly from skeletal than cardiac muscles. CONCLUSION: The acetate activation was mapped with hyperpolarized [1-(13) C]acetate in a clinical 3T system. Quantitative measurement of the activity was possible in the heart, indicating that dobutamine induced stress does not improve the ALCAR SNR in the heart.

Bolus tracking for improved metabolic imaging of hyperpolarised compounds.

Dynamic nuclear polarisation has enabled real-time metabolic imaging of pyruvate and its metabolites. Conventional imaging sequences rely on predefined settings and do not account for intersubject variations in biological parameters such as perfusion. We present a fully automatic real-time bolus tracking sequence for hyperpolarised substrates which starts the imaging acquisition at a defined point on the bolus curve. This reduces artefacts due to signal change and allows for a more efficient use of hyperpolarised magnetisation. For single time point imaging methods, bolus tracking enables a more reliable and consistent quantification of metabolic activity. An RF excitation with a small flip angle is used to obtain slice-selective pyruvate tracking information in rats. Moreover, in combination with a copolarised urea and pyruvate injection, spectrally selective tracking on urea allows obtaining localised bolus tracking information without depleting the pyruvate signal. Particularly with regard to clinical application, the bolus tracking technique could provide an important step towards a routine assessment protocol which removes operator dependencies and ensures comparable results.