Parahydrogen-Polarized Fumarate for Preclinical in Vivo Metabolic Magnetic Resonance Imaging

Martin Gierse, Luca Nagel, Michael Keim, Sebastian Lucas, Tobias Speidel, Tobias Lobmeyer, Gordon Winter, Felix Josten, Senay Karaali, Maximilian Fellermann, Jochen Scheuer, Christoph Müller, Frits van Heijster, Jason Skinner, Jessica Löffler, Anna Parker, Jonas Handwerker, Alastair Marshall, Alon Salhov, Bilal El-KassemChristophoros Vassiliou, John W. Blanchard, Román Picazo-Frutos, James Eills, Holger Barth, Fedor Jelezko, Volker Rasche, Franz Schilling, Ilai Schwartz, Stephan Knecht

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5960-5969
Number of pages10
JournalJournal of the American Chemical Society
Volume145
Issue number10
DOIs
StatePublished - 15 Mar 2023
Externally publishedYes

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