Mark Van Criekinge

This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-¹³C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo ¹³C MR data, it is possible to evaluate the distribution of agents such as [1-¹³C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-¹³C]lactate in tumor, with the ratio of [1-¹³C]lactate/[1-¹³C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect ¹³C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-¹³C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-¹³C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-¹³C]lactate/[1-¹³C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Purpose Hyperpolarized carbon‐13 ( 13 C) metabolic imaging is a noninvasive imaging modality for evaluating real‐time metabolism. The purpose of this study was to develop and implement experimental strategies for using [1‐ 13 C]pyruvate to probe in vivo metabolism for patients with brain tumors and other neurological diseases. Methods The 13 C radiofrequency coils and pulse sequences were tested in a phantom and were performed using a 3 Tesla whole‐body scanner. Samples of [1‐ 13 C]pyruvate were polarized using a SPINlab system. Dynamic 13 C data were acquired from 8 patients previously diagnosed with brain tumors, who had received treatment and were being followed with serial magnetic resonance scans. Results The phantom studies produced good‐quality spectra with a reduction in signal intensity in the center attributed to the reception profiles of the 13 C receive coils. Dynamic data obtained from a 3‐cm slice through a patient's brain following injection with [1‐ 13 C]pyruvate showed the anticipated arrival of the agent, its conversion to lactate and bicarbonate, and subsequent reduction in signal intensity. A similar temporal pattern was observed in 2D dynamic patient studies, with signals corresponding to pyruvate, lactate, and bicarbonate being in normal appearing brain, but only pyruvate and lactate being detected in regions corresponding to the anatomical lesion. Physiological monitoring and follow‐up confirmed that there were no adverse events associated with the injection. Conclusion This study has presented the first application of hyperpolarized 13 C metabolic imaging in patients with brain tumor and demonstrated the safety and feasibility of using hyperpolarized [1‐ 13 C]pyruvate to evaluate in vivo brain metabolism. Magn Reson Med 80:864–873, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

Hyperpolarized (13)C labeled molecular probes have been used to investigate metabolic pathways of interest as well as facilitate in vivo spectroscopic imaging by taking advantage of the dramatic signal enhancement provided by DNP. Due to the limited lifetime of the hyperpolarized nucleus, with signal decay dependent on T(1) relaxation, carboxylate carbons have been the primary targets for development of hyperpolarized metabolic probes. The use of these carbon nuclei makes it difficult to investigate upstream glycolytic processes, which have been related to both cancer metabolism as well as other metabolic abnormalities, such as fatty liver disease and diabetes. Glucose carbons have very short T(1)s (<1 s) and therefore cannot be used as an in vivo hyperpolarized metabolic probe of glycolysis. However, the pentose analogue fructose can also enter glycolysis through its phosphorylation by hexokinase and yield complementary information. The C(2) of fructose is a hemiketal that has a relatively longer relaxation time (approximately 16 s at 37 degrees C) and high solution state polarization (approximately 12%). Hyperpolarized [2-(13)C]-fructose was also injected into a transgenic model of prostate cancer (TRAMP) and demonstrated difference in uptake and metabolism in regions of tumor relative to surrounding tissue. Thus, this study demonstrates the first hyperpolarization of a carbohydrate carbon with a sufficient T(1) and solution state polarization for ex vivo spectroscopy and in vivo spectroscopic imaging studies.

MRI using hyperpolarized (HP) carbon‐13 pyruvate is being investigated in clinical trials to provide non‐invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1‐ 13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate‐to‐lactate conversion rate, k P L , as well as the lactate‐to‐pyruvate area‐under‐curve (AUC) ratio. The kinetic modeling included an “inputless” method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in k P L , signal‐to‐noise ratio (SNR), bolus characteristics, relaxation rates, and B 1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate k P L maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless k P L fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1‐ 13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1‐ 13 C]pyruvate parameters (SNR, k P L , bolus characteristics) in the human prostate.