Solvent effects in hyperpolarization of 15N nuclei in [15N3]metronidazole and [15N3]nimorazole antibiotics via SABRE-SHEATH

Metronidazole and nimorazole are antibiotics of a nitroimidazole group originally designed for acting on anaerobic bacteria. These antibiotics may be potentially utilized as hypoxia radiosensitizers for the treatment of cancerous tumors. Hyperpolarization of 15N nuclei in these compounds using SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei) approach provides dramatic enhancement of detection sensitivity of these analytes using magnetic resonance spectroscopy and imaging. Methanol-d4 is conventionally employed as a solvent in SABRE hyperpolarization process. Herein, we investigate SABRE-SHEATH hyperpolarization of isotopically labeled [15N3]metronidazole and [15N3]nimorazole in nondeuterated methanol-h4 and ethanol-h6 solvents (with the latter one being more preferable for biomedical applications due to its significantly lower toxicity). Optimization of hyperpolarization parameters, such as polarization transfer magnetic field, temperature, parahydrogen flow rate and pressure, allowed us to obtain an average 15N polarization of up to ca. 7.6% for both substrates. The highest 15N polarizations were observed in methanol-d4 for [15N3]metronidazole and in ethanol-h6 for [15N3]nimorazole. At a clinically relevant magnetic field of 1.4 T the 15N nuclei of these substrates possess long characteristic hyperpolarization lifetimes (T1) in the range from ca. 1 to ca. 7 min, with the longest relaxation observed for 15NO2 sites. This study represents a major step toward SABRE in more biocompatible solvents, such as ethanol, and also paves the way for future utilization of these hyperpolarized nitroimidazoles as molecular contrast agents for MRI visualization of tumors.