Clinically Translatable Hyperpolarized 13C Bicarbonate pH Imaging Method for Use in Prostate Cancer.

Solid tumors such as prostate cancer (PCa) commonly develop an acidic microenvironment with pH 6.5-7.2, owing to heterogeneous perfusion, high metabolic activity, and rapid cell proliferation. In preclinical prostate cancer models, disease progression is associated with a decrease in tumor extracellular pH, suggesting that pH imaging may reflect an imaging biomarker to detect aggressive and high-risk disease. Therefore, we developed a hyperpolarized carbon-13 MRI method to image the tumor extracellular pH (pHe) and prepared it for clinical translation for detection and risk stratification of PCa. This method relies on the rapid breakdown of hyperpolarized (HP) 1,2-glycerol carbonate (carbonyl-13C) via base-catalyzed hydrolysis to produce HP 13CO32-, which is neutralized and converted to HP H13CO3-. After injection, HP H13CO3- equilibrates with HP 13CO2 in vivo and enables the imaging of pHe. Using insights gleaned from mechanistic studies performed in the hyperpolarized state, we solved issues of polarization loss during preparation in a clinical polarizer system. We successfully customized a reaction apparatus suitable for clinical application, developed clinical standard operating procedures, and validated the radiofrequency pulse sequence and imaging data acquisition with a wide range of animal models. The results demonstrated that we can routinely produce a highly polarized and safe HP H13CO3- contrast agent suitable for human injection. Preclinical imaging studies validated the reliability and accuracy of measuring acidification in healthy kidney and prostate tumor tissue. These methods were used to support an Investigational New Drug application to the U.S. Food and Drug Administration. This methodology is now ready to be implemented in human trials, with the ultimate goal of improving the management of PCa.

Hyperpolarized Carbon 13 MRI: Clinical Applications and Future Directions in Oncology.

Hyperpolarized carbon 13 MRI (13C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology. Keywords: Hyperpolarized Carbon 13 MRI, Molecular Imaging, Cancer, Tissue Metabolism © RSNA, 2023.

Hyperpolarized Metabolic MRI-Acquisition, Reconstruction, and Analysis Methods.

Hyperpolarized metabolic MRI with 13C-labeled agents has emerged as a powerful technique for in vivo assessments of real-time metabolism that can be used across scales of cells, tissue slices, animal models, and human subjects. Hyperpolarized contrast agents have unique properties compared to conventional MRI scanning and MRI contrast agents that require specialized imaging methods. Hyperpolarized contrast agents have a limited amount of available signal, irreversible decay back to thermal equilibrium, bolus injection and perfusion kinetics, cellular uptake and metabolic conversion kinetics, and frequency shifts between metabolites. This article describes state-of-the-art methods for hyperpolarized metabolic MRI, summarizing data acquisition, reconstruction, and analysis methods in order to guide the design and execution of studies.

Combined 23 Na and 13 C imaging at 3.0 Tesla using a single-tuned large FOV birdcage coil.

PURPOSE: An unmet need in carbon-13 (13 C)-MRI is a transmit system that provides uniform excitation across a large FOV and can accommodate patients of wide-ranging body habitus. Due to the small difference between the resonant frequencies, sodium-23 (23 Na) coil developments can inform 13 C coil design while being simpler to assess due to the higher naturally abundant 23 Na signal. Here we present a removable 23 Na birdcage, which also allows operation as a 13 C abdominal coil. METHODS: We demonstrate a quadrature-driven 4-rung 23 Na birdcage coil of 50 cm in length for both 23 Na and 13 C abdominal imaging. The coil transmit efficiencies and B1+ maps were compared to a linearly driven 13 C Helmholtz-based (clamshell) coil. SNR was investigated with 23 Na and 13 C data using an 8-channel 13 C receive array within the 23 Na birdcage. RESULTS: The 23 Na birdcage longitudinal FOV was > 40 cm, whereas the 13 C clamshell was < 32 cm. The transmit efficiency of the birdcage at the 23 Na frequency was 0.65 µT/sqrt(W), similar to the clamshell for 13 C. However, the coefficient of variation of 23 Na- B1+ was 16%, nearly half that with the 13 C clamshell. The 8-channel 13 C receive array combined with the 23 Na birdcage coil generated a greater than twofold increase in 23 Na-SNR from the central abdomen compared with the birdcage alone. DISCUSSION: This 23 Na birdcage coil has a larger FOV and improved B1+ uniformity when compared to the widely used clamshell coil design while also providing similar transmit efficiency. The coil has the potential to be used for both 23 Na and 13 C imaging.

Comprehensive Literature Review of Hyperpolarized Carbon-13 MRI: The Road to Clinical Application.

This review provides a comprehensive assessment of the development of hyperpolarized (HP) carbon-13 metabolic MRI from the early days to the present with a focus on clinical applications. The status and upcoming challenges of translating HP carbon-13 into clinical application are reviewed, along with the complexity, technical advancements, and future directions. The road to clinical application is discussed regarding clinical needs and technological advancements, highlighting the most recent successes of metabolic imaging with hyperpolarized carbon-13 MRI. Given the current state of hyperpolarized carbon-13 MRI, the conclusion of this review is that the workflow for hyperpolarized carbon-13 MRI is the limiting factor.

Assessment of mouse liver [1-13C]pyruvate metabolism by dynamic hyperpolarized MRS.

Hyperpolarized [1-13C]pyruvate magnetic resonance (MR) spectroscopy has the unique ability to detect real-time metabolic changes in vivo owing to its high sensitivity compared with thermal MR and high specificity compared with other metabolic imaging methods. The aim of this study was to explore the potential of hyperpolarized MR spectroscopy for quantification of liver pyruvate metabolism during a hyperinsulinemic-isoglycemic clamp in mice. Hyperpolarized [1-13C]pyruvate was used for in vivo MR spectroscopy of liver pyruvate metabolism in mice. Mice were divided into two groups: (i) non-stimulated 5-h fasted mice and (ii) hyperinsulinemic-isoglycemic clamped mice. During clamp conditions, insulin and donor blood were administered at a constant rate, whereas glucose was infused to maintain isoglycemia. When steady state was reached, insulin-stimulated mice were rapidly infused with hyperpolarized [1-13C]pyruvate for real-time tracking of the dynamic distribution of metabolic derivatives from pyruvate, such as [1-13C]lactate, [1-13C]alanine and [13C]bicarbonate. Isotopomer analysis of plasma glucose confirmed 13C-incorporation from [1-13C]pyruvate into glucose was increased in fasted mice compared with insulin-stimulated mice, demonstrating an increased gluconeogenesis in fasted mice. The AUC ratios for [1-13C]alanine/[1-13C]pyruvate (38.2%), [1-13C]lactate/[1-13C]pyruvate (41.8%) and [13C]bicarbonate/[1-13C]pyruvate (169%) all increased significantly during insulin stimulation. Hyperpolarized [1-13C]pyruvate can be used for in vivo MR spectroscopy of liver pyruvate metabolism during hyperinsulinemic-isoglycemic clamp conditions. Under these conditions, insulin decreased gluconeogenesis and increased [1-13C]alanine, [1-13C]lactate and [13C]bicarbonate after a [1-13C]pyruvate bolus. This application of in vivo spectroscopy has the potential to identify impairments in specific metabolic pathways in the liver associated with obesity, insulin resistance and nonalcoholic fatty liver disease.

Handheld electromagnet carrier for transfer of hyperpolarized carbon-13 samples.

PURPOSE: Hyperpolarization of carbon-13 ((13) C) nuclei by dissolution dynamic nuclear polarization increases signal-to-noise ratio (SNR) by >10,000-fold for metabolic imaging, but care must be taken when transferring hyperpolarized (HP) samples from polarizer to MR scanner. Some (13) C substrates relax rapidly in low ambient magnetic fields. A handheld electromagnet carrier was designed and constructed to preserve polarization by maintaining a sufficient field during sample transfer. METHODS: The device was constructed with a solenoidal electromagnet, powered by a nonmagnetic battery, holding the HP sample during transfer. A specially designed switch automated deactivation of the field once transfer was complete. Phantom and rat experiments were performed to compare MR signal enhancement with or without the device for HP [(13) C]urea and [1-(13) C]pyruvate. RESULTS: The magnetic field generated by this device was tested to be >50 G over a 6-cm central section. In phantom and rat experiments, [(13) C]urea transported via the device showed SNR improvement by a factor of 1.8-1.9 over samples transferred through the background field. CONCLUSION: A device was designed and built to provide a suitably high yet safe magnetic field to preserve hyperpolarization during sample transfer. Comparative testing demonstrated SNR improvements of approximately two-fold for [(13) C]urea while maintaining SNR for [1-(13) C]pyruvate.