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

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

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

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.      «

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...     »