Hyperpolarized 13C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen‐induced Polarization: A Proof‐of‐Concept in vivo Study

Hyperpolarized [1‐13C]fumarate is a promising magnetic resonance imaging (MRI) biomarker for cellular necrosis, which plays an important role in various disease and cancerous pathological processes. To demonstrate the feasibility of MRI of [1‐13C]fumarate metabolism using parahydrogen‐induced polarization (PHIP), a low‐cost alternative to dissolution dynamic nuclear polarization (dDNP), a cost‐effective and high‐yield synthetic pathway of hydrogenation precursor [1‐13C]acetylenedicarboxylate (ADC) was developed. The trans‐selectivity of the hydrogenation reaction of ADC using a ruthenium‐based catalyst was elucidated employing density functional theory (DFT) simulations. A simple PHIP set‐up was used to generate hyperpolarized [1‐13C]fumarate at sufficient 13C polarization for ex vivo detection of hyperpolarized 13C malate metabolized from fumarate in murine liver tissue homogenates, and in vivo 13C MR spectroscopy and imaging in a murine model of acetaminophen‐induced hepatitis. Toward clinical translation: Hyperpolarized [1‐13C]fumarate was prepared by the trans‐selective para‐hydrogenation of [1‐13C] acetylenedicarboxylate precursor using a [Cp*Ru(MeCN)3]PF6 catalyst. The feasibility of in vivo imaging of necrotic cell death by 13C MRI of PHIP‐hyperpolarized exogenously injected fumarate metabolism was demonstrated in an acetaminophen‐induced hepatitis mouse.