We present a versatile method for the preparation of hyperpolarized [1-13C]fumarate as a contrast agent for preclinical in vivo MRI, using parahydrogen-induced polarization (PHIP). To benchmark this process, we compared a prototype PHIP polarizer to a state-of-the-art dissolution dynamic nuclear polarization (d-DNP) system. We found comparable polarization, volume, and concentration levels of the prepared solutions, while the preparation effort is significantly lower for the PHIP process, which can provide a preclinical dose every 10 min, opposed to around 90 min for d-DNP systems. With our approach, a 100 mM [1-13C]-fumarate solution of volumes up to 3 mL with 13-20% 13C-hyperpolarization after purification can be produced. The purified solution has a physiological pH, while the catalyst, the reaction side products, and the precursor material concentrations are reduced to nontoxic levels, as confirmed in a panel of cytotoxicity studies. The in vivo usage of the hyperpolarized fumarate as a perfusion agent in healthy mice and the metabolic conversion of fumarate to malate in tumor-bearing mice developing regions with necrotic cell death is demonstrated. Furthermore, we present a one-step synthesis to produce the 13C-labeled precursor for the hydrogenation reaction with high yield, starting from 13CO2 as a cost-effective source for 13C-labeled compounds.
Gierse M, Nagel L, Keim M, Lucas S, Speidel T, Lobmeyer T, Winter G, Josten F, Karaali S, Fellermann M, Scheuer J, Müller C, van Heijster F, Skinner J, Löffler J, Parker A, Handwerker J, Marshall A, Salhov A, El-Kassem B, Vassiliou C, Blanchard JW, Picazo-Frutos R, Eills J, Barth H, Jelezko F, Rasche V, Schilling F, Schwartz I, Knecht S. Parahydrogen-Polarized Fumarate for Preclinical in Vivo Metabolic Magnetic Resonance Imaging. J Am Chem Soc. 2023 Mar 1. doi: 10.1021/jacs.2c13830. Epub ahead of print. PMID: 36857421.