Hyperpolarized 13C MRI: State of the Art and Future Directions

Abstract

Hyperpolarized (HP) carbon 13 (¹³C) MRI is an emerging molecular imaging method that allows rapid, noninvasive, and pathway-specific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging. This technique has enabled real-time in vivo investigations of metabolism that are central to a variety of diseases, including cancer, cardiovascular disease, and metabolic diseases of the liver and kidney. This review provides an overview of the methods of hyperpolarization and ¹³C probes investigated to date in preclinical models of disease. The article then discusses the progress that has been made in translating this technology for clinical investigation. In particular, the potential roles and emerging clinical applications of HP [1-¹³C]pyruvate MRI will be highlighted. The future directions to enable the adoption of this technology to advance the basic understanding of metabolism, to improve disease diagnosis, and to accelerate treatment assessment are also detailed.

Figure 1:

Processes for increasing MRI signal of carbon 13 (¹³C) nuclei. DNP = dynamic nuclear polarization, NMR = nuclear magnetic resonance.

Figure 2:

Schematic of the metabolic pathways of pyruvate. [1-¹³C]pyruvate is rapidly taken up into the cells and metabolized within the cytosol into [1-¹³C]lactate and [1-¹³C]alanine by the enzymes lactate dehydrogenase (LDH) and alanine transaminase (ALT), respectively. Hyperpolarized [1-¹³C]pyruvate is also transported into the mitochondria and is converted by the enzyme pyruvate dehydrogenase (PDH) into ¹³C CO₂ and acetyl Co-A, with CO₂ in rapid equilibrium with ¹³C bicarbonate. TCA = tricarboxylic acid. Red circle = position of ¹³C labeling.

Figure 3:

Hyperpolarized (HP) carbon 13 (¹³C) MRI in a transgenic adenocarcinoma mouse model of prostate cancer. A, Representative hematoxylin-eosin–stained pathology sections and HP ¹³C spectra after injection of HP [1-¹³C]pyruvate in a normal mouse prostate, an early-stage prostate tumor, a late-stage prostate tumor, and a lymph node metastasis. At histologic examination, normal murine prostate was glandular, with secretory epithelial cells lining the glands (arrowhead). In prostate tumors, there was gradual replacement of the secretory epithelial cells by less differentiated epithelial cells, until the glands were completely eliminated and only anaplastic sheets of pleomorphic cells with irregular nuclei remained in the late stage tumors (arrow). The ¹³C spectra show an increase in ¹³C lactate and ¹³C lactate/pyruvate ratio in late-stage tumor and nodal metastasis. B, Axial T2-weighted anatomic MR image and overlay of HP ¹³C lactate image on T2-weighted image show a qualitatively high level of lactate in a late-stage tumor. Units for color bar = arbitrary units of signal intensity. C, Boxplots show quantitative ¹³C lactate signal in the four histologically defined groups, with late-stage tumors having significantly higher lactate than early-stage tumors. SNR = signal-to-noise ratio. (Adapted from reference .)

Figure 4:

Schematic shows the required components for clinical hyperpolarized carbon 13 (¹³C) MRI studies. The pharmacy kits used for preparing sterile ¹³C probes, the clinical polarizers with built-in quality-control units, and specialized MRI detector hardware are now commercially available. Many of the fast ¹³C pulse sequences and postprocessing tools are available as open source. In the case of [1-¹³C]pyruvate, the Investigational New Drug resource for its use is available from the National Cancer Institute to assist sites in obtaining U.S. Food and Drug Administration (FDA) regulatory approval for clinical HP MRI studies. k_PL = apparent rate constant for pyruvate-to-lactate conversion.

Figure 5:

Representative axial T2-weighted MR image, water apparent diffusion coefficient (ADC) image, T2-weighted MR image with overlaid apparent rate constant for pyruvate (Pyr)-to-lactate (Lac) conversion (k_PL), and corresponding hyperpolarized (HP) carbon 13 (13C) spectral array in a 52-year-old patient with extensive high-grade (Gleason 4 + 5) prostate cancer, A, before therapy and, B, 6 weeks after initiation of androgen ablation and chemotherapy. Before treatment, the region of prostate cancer can be seen (arrows) as low signal on the T2-weighted and ADC images, with high HP lactate seen in the spectral array (vertical axis = arbitrary signal intensity units; horizontal axis = frequency in parts per million) and high k_PL. At 6 weeks after initiation of androgen deprivation therapy, there was near complete abrogation of elevated HP lactate peaks on the spectral array and associated marked reduction in tumor k_PL (maximum k_PL, 0.025 sec²¹ at baseline and 0.007 sec²¹ at follow-up). Notably, there was negligible change in the size of tumor on T2-weighted MR images and only a modest change on ADC images, supporting the utility of HP [1-¹³C]pyruvate MRI in detecting early metabolic responses prior to changes on conventional images. Concordant with these findings, the patient subsequently achieved a marked clinical response, with an undetectable serum prostate-specific antigen level 6 months after treatment initiation. (Reprinted, with permission, from reference .)

Figure 6:

Hyperpolarized (HP) [1-¹³C]pyruvate MR images in two patients with treated glioblastoma multiforme. Patient A (top row) had progressing tumor at the time of the HP study, while patient B (bottom row) had stable tumor at the time of the HP study. HP [1-¹³C]pyruvate was rapidly transported across the blood-brain barrier and converted to the metabolites lactate and bicarbonate. There was substantial pyruvate-to-lactate and pyruvate-to-bicarbonate conversion in the normal brain. The tumor (arrows) in patient A, who had progressive tumor, showed moderate pyruvate-to-lactate conversion when compared with normal brain. The tumor (arrow) in patient B, who had clinically stable tumor, showed no substantial pyruvate-to-lactate conversion. Both tumors showed a lack of pyruvate-to-bicarbonate conversion, suggesting reduced mitochondrial oxidative metabolism. Color bars = metabolite ratios. The differences in the scales of the color bars are due to the single-band constant flip angle excitation scheme used for patient A and the multiband variable flip angle excitation scheme used for patient B. These initial findings support the use of HP [1-¹³C]pyruvate MRI for investigating metabolic reprogramming in brain tumors. FLAIR = fluid-attenuated inversion recovery, Gad = gadolinium. (Reprinted from reference .)

Figure 7:

Hyperpolarized (HP) [1-¹³C]pyruvate MR images in a patient with breast cancer metastatic to the liver. The study was performed by using a 16-channel abdomen carbon 13 (¹³C) coil array permitting coverage of the whole upper abdomen and a dynamic ¹³C echo-planar spectroscopic imaging technique at a 2-second time resolution. T2-weighted single-shot fast spin-echo (SSFSE) image (left) shows multiple liver metastases. The k_PL (the apparent rate constant for pyruvate-to-lactate conversion in sec²¹) map overlaid on the T2-weighted SSFSE image (right) shows liver metastases (arrows) with elevated pyruvate-to-lactate conversion, consistent with metabolically active tumors.