15N NMR Hyperpolarization of Radiosensitizing Antibiotic Nimorazole via Reversible Parahydrogen Exchange in Microtesla Magnetic Fields

• Published in: Angewandte Chemie International Edition Vol. 60; no. 5; pp. 2406 - 2413
• Main Authors: Salnikov, Oleg G., Chukanov, Nikita V., Svyatova, Alexandra, Trofimov, Ivan A., Kabir, Mohammad S. H., Gelovani, Juri G., Kovtunov, Kirill V., Koptyug, Igor V., Chekmenev, Eduard Y.
• Format: Journal Article
• Language: English
• Published: 01.12.2020
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202011698

Nimorazole belongs to the imidazole-based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [ 15 N 3 ]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next-generation MRI-LINAC systems. Here, we report the first but very important steps to create long-lasting (for tens of minutes) hyperpolarized state on three 15 N sites of [ 15 N 3 ]nimorazole with T 1 of up to ~6 minutes. The nuclear spin polarization was boosted by ~67000-fold at 1.4 T (corresponding to P 15N of 3.2%) via 15 N- 15 N spin-relayed SABRE-SHEATH hyperpolarization technique relying on simultaneous exchange of [ 15 N 3 ]nimorazole and parahydrogen on polarization transfer Ir-IMes catalyst. The isomeric side product of [ 15 N 3 ]nimorazole synthesis was hyperpolarized too. The presented results pave the way to efficient spin-relayed SABRE-SHEATH hyperpolarization of a wide range of imidazole-based antibiotics and chemotherapeutics. Synthesis of 15 N 3 -enriched antibiotic and hypoxic radiosensitizer nimorazole is reported. Spin-relayed Signal Amplification By Reversible Exchange in microtesla magnetic field yielded up to 3.2% 15 N nuclear spin polarization with relaxation time constant of 5.9 ± 0.2 min at 1.4 T. The isomer of nimorazole formed in the synthesis was also hyperpolarized indicating that this approach can be extended to a wide range of nitroimidazole-based drugs.