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.

An extraordinary new technique using hyperpolarized 13 Clabeled pyruvate and taking advantage of increased glycolysis in cancer has the potential to improve the way magnetic resonance imaging is used for detection and characterization of prostate cancer. The aim of this study was to quantify, for the first time, differences in hyperpolarized [1-13 C] pyruvate and its metabolic products between the various histologic grades of prostate cancer using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Fast spectroscopic imaging techniques were used to image lactate, alanine, and total hyperpolarized carbon (THC = lactate + pyruvate + alanine) from the entire abdomen of normal mice and TRAMP mice with low-and high-grade prostate tumors in 14 s. Within 1 week, the mice were dissected and the tumors were histologically analyzed. Hyperpolarized lactate SNR levels significantly increased (P < 0.05) with cancer development and progression (41 F 11, 74 F 17, and 154 F 24 in normal prostates, low-grade primary tumors, and high-grade primary tumors, respectively) and had a correlation coefficient of 0.95 with the histologic grade. In addition, there was minimal overlap in the lactate levels between the three groups with only one of the seven normal prostates overlapping with the low-grade primary tumors. The amount of THC, a possible measure of substrate uptake, and hyperpolarized alanine also increased with tumor grade but showed more overlap between the groups. In summary, elevated hyperpolarized lactate and potentially THC and alanine are noninvasive biomarkers of prostate cancer presence and histologic grade that could be used in future three-dimensional 13 C spectroscopic imaging studies of prostate cancer patients. [Cancer Res 2008;68(20):8607-15]

The transgenic adenocarcinoma of mouse prostate (TRAMP) mouse is a well-studied murine model of prostate cancer with histopathology and disease progression that mimic the human disease. To investigate differences in cellular bioenergetics between normal prostate epithelial cells and prostate tumor cells, in vivo MR spectroscopic (MRS) studies with non-proton nuclei, such as 13 C, in the TRAMP model would be extremely useful. The recent development of a method for retaining dynamic nuclear polarization (DNP) in solution permits high signal-tonoise ratio (SNR) 13 C MRI or MRSI data to be obtained following injection of a hyperpolarized 13 C agent. In this transgenic mouse study, this method was applied using a double spinecho (DSE) pulse sequence with a small-tip-angle excitation RF pulse, hyperbolic-secant refocusing pulses, and a flyback echo-planar readout trajectory for fast (10 -14 s) MRSI of 13 C pyruvate (pyr) and its metabolic products at 0.135 cm 3 nominal spatial resolution. The transgenic adenocarcinoma of mouse prostate (TRAMP) mouse is an established and well-studied murine model of prostate cancer (1,2). The histopathology of TRAMP mouse cancer tissue mimics that of human disease. TRAMP mice develop spontaneous progressive disease that begins with prostatic intraepithelial neoplasia (PIN) and then advances to frank carcinoma lesions in the prostatic lobes. The cancer also frequently metastasizes in this model to the lymph nodes (LN) and lungs, and, to a lesser extent, to the kidneys, adrenal glands, liver, and bone (2). The TRAMP model is being used in numerous laboratories to identify the molecular mechanisms associated with the initiation and progression of metastatic prostate cancer. Currently, almost all TRAMP studies use histopathology as the only parameter to evaluate the progression of the disease as well as the efficacy of the treatment agent being tested. Although this parameter is very useful and informative, the mouse has to be killed. Having a noninvasive, in vivo method would be valuable for following disease progression and treatment response in the same animal. TRAMP mice also serve as a good model system for testing new methods to characterize human prostate cancers.Combined proton MRI and MR spectroscopic imaging (MRSI) exams have become routine clinical procedures for characterizing prostate cancer in humans (3-6). In particular, proton MRSI allows identification of changes associated with prostate cancer biomarkers, such as an increase in choline and a reduction in citrate. Single-voxel proton MRS data have been demonstrated in the TRAMP model (7), but this required a 7T animal MR system and an extremely long acquisition time (ϳ2 hr for a single-voxel spectrum). Studying cellular bioenergetics in the TRAMP mouse would also benefit from in vivo MRS studies with non-proton nuclei, such as 13 C, but due to the low natural abundance of 13 C and its low sensitivity compared to the proton, the signal-to-noise ratio (SNR) is prohibitively low in small animals. With the recent development ...

Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response. Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors. http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg .

We present for the first time dynamic spectra and spectroscopic images acquired in normal rats at 3T following the injection of 13 C-1-pyruvate that was hyperpolarized by the dynamic nuclear polarization (DNP) method. Spectroscopic sampling was optimized for signal-to-noise ratio (SNR) and for spectral resolution of 13 C-1-pyruvate and its metabolic products 13 C-1-alanine, 13 C-1-lactate, and 13 C-bicarbonate. Dynamic spectra in rats were collected with a temporal resolution of 3 s from a 90-mm axial slab using a dual 1 H-13 C quadrature birdcage coil to observe the combined effects of metabolism, flow, and T 1 relaxation. In separate experiments, spectroscopic imaging data were obtained during a 17-s acquisition of a 20-mm axial slice centered on the rat kidney region to provide information on the spatial distribution of the metabolites. Conversion of pyruvate to lactate, alanine, and bicarbonate occurred within a minute of injection. Alanine was observed primarily in skeletal muscle and liver, while pyruvate, lactate, and bicarbonate concentrations were relatively high in the vasculature and kidneys. In contrast to earlier work at 1. Historically, magnetic resonance (MR) has been a technique associated with low sensitivity, limited by small differences in energy-state populations dictated by the Boltzmann distribution. Increases in magnetic field strength provide modest improvements in the population distribution and thus the sensitivity, but the polarization at thermal equilibrium is fundamentally limited by the low nuclear gyromagnetic ratios. Applications of MRI have thus been focused on imaging the 1 H nucleus occurring in very high concentrations in fat and water in vivo. Clinical 1 H spectroscopy has been possible for metabolites in relatively high concentrations, while spectroscopy of nuclei with lower gyromagnetic ratios, and thus less favorable population distributions, has been difficult at best.Methods to produce substantially altered population distributions or "hyperpolarization" by dynamic nuclear polarization (DNP) and other techniques have been known for a long time (1-6), but have not been applicable to in vivo studies due to the necessity of polarization at very low temperatures (1.2 K) and high fields. The recent development of techniques to achieve high polarization in the solid state and retain a high degree of polarization through fast dissolution procedures (7-9) has provided a mechanism to produce enhancements of MR signals by up to five orders of magnitude compared to thermal equilibrium at typical MR field strengths, thus providing the possibility of directly imaging metabolites of low concentration in vivo. In addition, the potential now exists for directly observing low concentrations of 13 C-labeled compounds in vivo and following their metabolism over short periods of time. Prior studies performed at 1.5T (10,11) have demonstrated the use of hyperpolarized 13 C-labeled pyruvate to directly monitor metabolism in vivo, and to observe the conversion of pyruvate to lactate and alanin...