Hyperpolarized MRI - outline

importance

Hyperpolarized MRI is an emerging method “with the ability to transiently enhance the MR signal of 13C-enriched molecules by > 10.000 times.” ¹

• uniquely positioned between the conventional MRI and positron emission tomography (PET)²
  • “Unlike conventional MRI, which visualizes anatomical structures using 1H nuclei, HP MRI uses labeled compounds with significantly enhanced nuclear spin polarization” (Hsieh et al., 2025, p. 1)
  • “In contrast to PET-FDG (18F-fluorodeoxyglucose), which tracks glucose metabolism using radioactive tracers, HP 13C MRI is non-radioactive and provides a different metabolic perspective.” (Hsieh et al., 2025, p. 1) Also PET-FDG cannot help assess downstream metabolism or distinguish different metabolic pathways unlike HP 13C MRI ²³¹
• role of HP 13C pyruvate
  • in translational research, researchers utilize it to visualize how diseases alter metabolic pathways, and to assess the metabolic effects of experimental drugs or interventions in preclinical studies. E.g. monitoring the conversion of pyruvate to lacate in cancer cells (Warburg effect) and seeing how a new cancer drug affects lactate production in tumor models ²
  • In clinical practice, “HP 13C pyruvate MRI is applied directly to patients to diagnose disease, guide treatment decisions, monitor therapeutic response, and evaluate disease progression.” (Hsieh et al., 2025, p. 2)
  • offers the advantage of detecting metabolic changes much earlier than changes in tumor size in a quick real-time non-invasive tracking of disease progression ²⁴

“Hyperpolarized (HP) 13C MRI has emerged as a powerful molecular imaging strategy that allows safe, nonradioactive, real-time, and pathway-specific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging.” ³(p. 273)

HP MRI has an overwhelming promise to revolutionize medical diagnostic imaging. Efforts are ongoing to improve the technique, investigate new applications and evaluate the clinical value with more than 20 ongoing clinical trials focusing on HP 13C pyruvate, in order to allow more widespread and reliable use of the imaging modality ⁴

“a feasibility study of treatment response in breast cancer showed that hyperpolarized 13C pyruvate MRSI was able to identify metabolic changes after only one cycle of neoadjuvant chemotherapy” and so this treatment could be used in detecting early treatment response and allow early adaption of therapy in non-responders ¹

“for the technology to become scalable and impactful, the hyperpolarized 13C MR technology has to be easy to use, regardless of the specific methodology and equipment employed.” ⁴

• progress is being made to make polarization techniques more standardized and streamlined ⁴

“Combined with the already widely established and available MRI infrastructure, hyperpolarized MRI has the potential to scale up quickly to more widespread usage.” (Chaumeil et al., 2024, p. 228)

Physics behind HP MRI

• At the body temp and field strengths used in clinical MRI, the MRI signal of 13C nuclei is very low because of of its natural low abundance (1.1% of carbon is 13C ¹) and its low spin polarization (the spins are not aligned to the external magnetic field ³

  • “At body temperature the polarization level of 13C is 0.0005 %, producing a very low MR signal.” ¹

• This limitation has been overcome by recent development of  hyper-polarization methods that temporarily increase the signal of 13C

• enrichment = “To improve the MRI signal of 13C nuclei, probes can be synthetically enriched to increase the concentration of the 13C label in a molecule, commonly enriched to 99% of 13C.” ³

• principle of hyper-polarization = “based on the fact that at low temperature and high magnetic field, electrons have a very high level of polarization (ie, nearly all the electrons are aligned in the same direction).”³

• Dynamic nuclear polarization = “transfer of polarization is accomplished by mixing radicals (a source of free electrons) with the 13C-labeled probe(s) to be hyperpolarized and placing the mixture in a polarizer at a magnetic field typically of 3.0–5.0 T and at a low temperature (approximately 1 K).” ³

• “Microwave irradiation is then applied to transfer the polarization from unpaired electrons in a trityl radical to the 13C-labeled probes” ³

• before hyper-polarization, 13C thermal equilibrium polarization is approx 0.00025% aligned with external magnetic field; after hyper-polarization, it increases to 30% - 40% (100 000 fold increase)³

• hyper-polarization process takes between 30 to 120 minutes

• “The enhanced MR signal decays rapidly (1-2 minutes) and imaging must be performed immediately to acquire high signal-to-noise metabolic data” ¹ Pyruvate

• “polarizes well (up to 50% polarization level in current clinical polarizers)”

• has a long T1 (approximately 67 seconds in solution at 3.0 T), thereby permitting in vivo investigation with high signal-to-noise ratio.

  • “the T1 determines how quickly the polarization of the probe decays back to thermal equilibrium once it is removed from the polarizer. Longer T1 facilitates preservation of the enhanced MRI signal and therefore more accurate quantification of metabolism in vivo.”³

• Importantly, HP 13C pyruvate is a highly biologically relevant probe, as pyruvate lies at a critical branch point of multiple metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid biosynthesis” ³

• “Pyruvate is the end-product of intracellular glycolysis.” ¹

• “increase in aerobic glycolysis and lactate production, also known as the Warburg effect, is characteristic of many tumors.” ³

• “Imaging of the increased conversion of [1-13C]pyruvate to [1-13C] lactate has been proposed as a promising method to diagnose early cancer and to detect treatment response” ¹

Limitations

“A major obstacle in the dissemination of hyperpolarized MRSI has been the fact that hyperpolarization is both a time consuming and a technically challenging process, requiring specially trained personnel with expertise in producing hyperpolarized probes, monitoring their quality, and assuring patient safety and regulatory compliance.3 Further, interpretation of data requires trained staff members and physicians.” (Jørgensen et al., 2022, p. 379)

“PHIP is still experimental, but the method has the potential to become more cost-effective than dDNP and PHIP can achieve polarization faster than dDNP” (Jørgensen et al., 2022, p. 379)

Footnotes

1. Jørgensen et al., 2022 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

2. Hseich et al, 2005 ↩ ↩² ↩³ ↩⁴

3. Wang et al, 2019 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹

4. Chaumil et al, 2024 ↩ ↩² ↩³ ↩⁴