In Vivo Metabolic Imaging of [1-13 C]Pyruvate-d3 Hyperpolarized By Reversible Exchange With Parahydrogen.

Metabolic magnetic resonance imaging (MRI) using hyperpolarized (HP) pyruvate is becoming a non-invasive technique for diagnosing, staging, and monitoring response to treatment in cancer and other diseases. The clinically established method for producing HP pyruvate, dissolution dynamic nuclear polarization, however, is rather complex and slow. Signal Amplification By Reversible Exchange (SABRE) is an ultra-fast and low-cost method based on fast chemical exchange. Here, for the first time, we demonstrate not only in vivo utility, but also metabolic MRI with SABRE. We present a novel routine to produce aqueous HP [1-13 C]pyruvate-d3 for injection in 6 minutes. The injected solution was sterile, non-toxic, pH neutral and contained ≈30 mM [1-13 C]pyruvate-d3 polarized to ≈11 % (residual 250 mM methanol and 20 µM catalyst). It was obtained by rapid solvent evaporation and metal filtering, which we detail in this manuscript. This achievement makes HP pyruvate MRI available to a wide biomedical community for fast metabolic imaging of living organisms.

Rapid in situ carbon-13 hyperpolarization and imaging of acetate and pyruvate esters without external polarizer.

Hyperpolarized 13C MRI visualizes real-time metabolic processes in vivo. In this study, we achieved high 13C polarization in situ in the bore of an MRI system for precursor molecules of most widely employed hyperpolarized agents: [1-13C]acetate and [1-13C]pyruvate ethyl esters in their perdeuterated forms, enhancing hyperpolarization lifetimes, hyperpolarized to P13C ≈ 28% at 80 mM concentration and P13C ≈ 19% at 10 mM concentration, respectively. Using vinyl esters as unsaturated Parahydrogen-Induced Polarization via Side-Arm Hydrogenation (PHIP-SAH) precursors and our novel polarization setup, we achieved these hyperpolarization levels by fast side-arm hydrogenation in acetone-d6 at elevated temperatures (up to 90°C) and hydrogenation pressures (up to 32 bar). We optimized the hyperpolarization process, reducing it to under 10 s, and employed advanced pulse sequences to enhance the polarization transfer efficiency. The hyperpolarization system has a small footprint, allowing it to be positioned in the same magnet, where 13C MRI is performed. We exemplified the utility of the design with sub-second in situ 13C MRI of ethyl [1-13C]pyruvate-d6. However, challenges remain in side-arm cleavage and purification in the MRI system to extract highly polarized aqueous agent solutions. Our results showcase efficient and rapid 13C hyperpolarization of these metabolite precursors in an MRI system with minimal additional hardware, promising to enhance future throughput and access to hyperpolarized 13C MRI.