Parahydrogen‐Polarized [1‐¹³C]Pyruvate for Reliable and Fast Preclinical Metabolic Magnetic Resonance Imaging

Abstract

Hyperpolarization techniques increase nuclear spin polarization by more than four orders of magnitude, enabling metabolic MRI. Even though hyperpolarization has shown clear value in clinical studies, the complexity, cost and slowness of current equipment limits its widespread use. Here, a polarization procedure of [1‐13C]pyruvate based on parahydrogen‐induced polarization by side‐arm hydrogenation (PHIP‐SAH) in an automated polarizer is demonstrated. It is benchmarked in a study with 48 animals against a commercial dissolution dynamic nuclear polarization (d‐DNP) device. Purified, concentrated (≈70–160 mM) and highly hyperpolarized (≈18%) solutions of pyruvate are obtained at physiological pH for volumes up to 2 mL within 85 s in an automated process. The safety profile, image quality, as well as the quantitative perfusion and lactate‐to‐pyruvate ratios, are equivalent for PHIP and d‐DNP, rendering PHIP a viable alternative to established hyperpolarization techniques.

Efficient Parahydrogen-Induced 13C Hyperpolarization on a Microfluidic Device

“…Preparation relies on either dissolution dynamic nuclear polarization 29,30 or on low-field polarization transfer based on parahydrogen-induced polarization (PHIP). 31,32 The batch mode of operation of these methods does not lend itself to LoC culture devices, where a steady supply of much smaller amounts of hyperpolarized metabolites is needed. In this case, preparation methods that operate continuously at flow rates compatible with microfluidic systems (up to a few μL/min) are required.…”

“…Hyperpolarized metabolites have great potential as contrast agents for magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI), providing real-time and quantitative information on active metabolic pathways in healthy and diseased tissues. , This approach has been used in vivo for metabolic profiling of tumors such glioma, , hepatocellular carcinoma, lymphoma, , pancreatic and breast cancers. , In this modality, relatively large amounts (several g) of hyperpolarized material (most commonly pyruvate) are prepared and injected intravenously into the patient. Preparation relies on either dissolution dynamic nuclear polarization , or on low-field polarization transfer based on parahydrogen-induced polarization (PHIP). , The batch mode of operation of these methods does not lend itself to LoC culture devices, where a steady supply of much smaller amounts of hyperpolarized metabolites is needed. In this case, preparation methods that operate continuously at flow rates compatible with microfluidic systems (up to a few μL/min) are required .…”

Carbon-13 Radiofrequency Amplification by Stimulated Emission of Radiation of the Hyperpolarized Ketone and Hemiketal Forms of Allyl [1-13C]Pyruvate

“…Several hyperpolarization techniques have succeeded in production and utilization of biocompatible 13 C HP contrast agents, including most prominently [1- 13 C]­pyruvate, which has been hyperpolarized by d-DNP, ,, PHIP, − and signal amplification by reversible exchange (SABRE). ,,,− It should be noted that d-DNP is the leading hyperpolarization technique and the only one that has matured to clinical studies and clinical trials. Biocompatible HP [1- 13 C]­pyruvate solution can be administered via injection, and, as illustrated in Scheme a, it is enzymatically converted mainly to HP [1- 13 C]­alanine (via transamination), [1- 13 C]­lactate (via reduction), 13 C-bicarbonate (via oxidative phosphorylation), and [1- 13 C]­pyruvate hydrate (via hydration) on the time scale of tens of seconds in vivo. ,,− As illustrated in Scheme b, the chemical shifts of HP [1- 13 C]­pyruvate and its HP metabolic products are different by as much as 12 ppm, and it becomes possible to distinguish each species via their chemical shift mapping .…”