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 which also may be potentially utilized as hypoxia radiosensitizers for the treatment of cancerous tumors. Hyperpolarization of N-15 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-d(4) is conventionally employed as a solvent in SABRE hyperpolarization process. Herein, we investigate SABRE-SHEATH hyperpolarization of isotopically labeled [N-15(3)]metronidazole and [N-15(3)]nimorazole in nondeuterated methanol and ethanol solvents. Optimization of such hyperpolarization parameters as polarization transfer magnetic field, temperature, parahydrogen flow rate and pressure allowed us to obtain an average N-15 polarization of up to 7.2-7.4 % for both substrates. The highest( 15)N polarizations were observed in methanol-d(4 )for [N-15(3)]metronidazole and in ethanol for [N-15(3)]nimorazole. At a clinically relevant magnetic field of 1.4 T the N-15 nuclei of these substrates possess long characteristic hyperpolarization lifetimes (T-1) of ca. 1 to ca. 7 min. 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.