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

Hyperpolarized [1‐(13)C]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‐(13)C]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‐(13)C]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‐(13)C]fumarate at sufficient (13)C polarization for ex vivo detection of hyperpolarized (13)C malate metabolized from fumarate in murine liver tissue homogenates, and in vivo (13)C MR spectroscopy and imaging in a murine model of acetaminophen‐induced hepatitis.