Hyperpolarized Carbon-13 Magnetic Resonance Imaging: Technical Considerations and Clinical Applications

Abstract

Hyperpolarized (HP) carbon-13 (¹³C) MRI represents an innovative approach for noninvasive, real-time assessment of dynamic metabolic flux, with potential integration into routine clinical MRI. The use of [1-¹³C]pyruvate as a probe and its conversion to [1-¹³C]lactate constitute an extensively explored metabolic pathway. This review comprehensively outlines the establishment of HP ¹³C-MRI, covering multidisciplinary team collaboration, hardware prerequisites, probe preparation, hyperpolarization techniques, imaging acquisition, and data analysis. This article discusses the clinical applications of HP ¹³C-MRI across various anatomical domains, including the brain, heart, skeletal muscle, breast, liver, kidney, pancreas, and prostate. Each section highlights the specific applications and findings pertinent to these regions, emphasizing the potential versatility of HP ¹³C-MRI in diverse clinical contexts. This review serves as a comprehensive update, bridging technical aspects with clinical applications and offering insights into the ongoing advancements in HP ¹³C-MRI.

Keywords: Carbon 13; Hyperpolarized; Lactate; Magnetic resonance imaging; Pyruvate.

Fig. 1. Principal metabolic pathways of [1-¹³C]pyruvate and [2-¹³C]pyruvate that were detected by hyperpolarized ¹³C-MRI. For comparison of the metabolic fates of pyruvate’s C1 and C2, the C1 and C2 ¹³C positions are indicated in yellow and orange, respectively. CA = carbonic anhydrase, PDH = pyruvate dehydrogenase, ALT = alanine transaminase, MCT = monocarboxylate transporter, LDH = lactate dehydrogenase

Fig. 2. Clinical workflow of hyperpolarized ¹³C-MRI. A: In a controlled, clean room equipped with a laminar flow hood, the drug was prepared by blending a ¹³C-labeled probe with EPAs and gadolinium. B: The pre-mixed drug was introduced into a sterile fluid path assembly, which included a dissolution syringe (containing sterile water for injection), a sample vial (housing the probe), an EPA filter, a receiver vessel (containing buffer solution), and an administration syringe for injection. C: A clinical polarizer, designed for human research, operates within a high magnetic field and an ultra-low-temperature environment. The buildup of polarization typically takes 2–3 hours to reach a polarization level of 20%–40%. D: Following the initiation of dissolution, superheated and pressurized water dissolved the solid-state sample, and the resulting solution underwent filtration and buffering processes. The solution, comprising the hyperpolarized probe, underwent meticulous quality control measures. E: The hyperpolarized probe was subsequently transported to an MRI scanner for administration in human subjects. The ¹³C signal was promptly and efficiently acquired using optimized pulse sequences. EPA = electron paramagnetic agent

Fig. 3. Representative data and key quantitative methods for pyruvate-to-lactate conversion in hyperpolarized ¹³C-MRI. A: A representative single timepoint ¹³C spectrum was dominated by the resonance from [1-¹³C]pyruvate (171 ppm), [1-¹³C]lactate (183 ppm), [1-¹³C]pyruvate hydrate (179 ppm), and [¹³C]bicarbonate (164 ppm). B: Stacked plot of dynamic ¹³C spectra with a temporal resolution of 2 s. C: Kinetic modeling involves creating a mathematical model to describe the conversion rates of ¹³C-labeled probes into various products. The conversion rate constant, often denoted as k_PL, serves as a key parameter for characterizing the speed of the pyruvate-to-lactate flux. D: Metabolite ratios, often in the form of AUC ratios, employ the AUC of the product as the numerator and either the substrate or the total ¹³C signal as the denominator, offering an alternative approach to evaluate the pyruvate-to-lactate flux. AUC = area under the curve

Fig. 4. Examples of clinical applications of hyperpolarized ¹³C-MRI, where pyruvate and lactate maps are overlayed with anatomic ¹H-MRI. A: Right cerebellar metastasis from renal cell carcinoma (arrows) (Adapted from Lee et al. J Neurooncol 2021;152:551-557 [28], with permission of CC BY 4.0 license). B: Right breast cancer (arrows) (Adapted from Woitek et al. Radiol Imaging Cancer 2020;2:e200017 [41], with permission of Radiological Society of North America). C: Renal cell carcinoma in the right kidney (Adapted from Ursprung et al. Cancers (Basel) 2022;14:335 [45], with permission of CC BY 4.0 license).

Fig. 5. Aligning HP ¹³C-MRI with established diagnostic procedures. A: The lactate signal-to-noise ratio map in the HP ¹³C-MRI (left panel) correlates to the histopathology analysis (right panel) and distinctly showcases a stronger lactate signal in the grade 3 prostate cancer located in the left peripheral zone, as opposed to the weaker signal observed in the grade 1 prostate cancer in the right transition zone, which illustrates of the correlation of the Warburg effect and the tumor grade (Adapted from Sushentsev et al. Nat Commun 2022;13:466 [55], with permission of CC BY 4.0 license). B: Comparative analysis of HP ¹³C-MRI and ¹⁸F-FDG PET/CT in assessing the left neck metastatic lymph node (level IV) from a patient with head and neck cancer. It shows a [1-¹³C]pyruvate map superimposed on a fat-suppressed T2-weighted image (right panel), alongside an ¹⁸F-FDG map overlaid on a CT scan (left panel). HP = hyperpolarized, FDG = 2-deoxy-2-[¹⁸F]fluoroglucose