Development of Dissolution Dynamic Nuclear Polarization of [15 N3 ]Metronidazole: A Clinically Approved Antibiotic

Abstract

We report dissolution Dynamic Nuclear Polarization (d-DNP) of [¹⁵ N₃ ]metronidazole ([¹⁵ N₃ ]MNZ) for the first time. Metronidazole is a clinically approved antibiotic, which can be potentially employed as a hypoxia-sensing molecular probe using ¹⁵ N hyperpolarized (HP) nucleus. The DNP process is very efficient for [¹⁵ N₃ ]MNZ with an exponential build-up constant of 13.8 min using trityl radical. After dissolution and sample transfer to a nearby 4.7 T Magnetic Resonance Imaging scanner, HP [¹⁵ N₃ ]MNZ lasted remarkably long with T₁ values up to 343 s and ¹⁵ N polarizations up to 6.4 %. A time series of HP [¹⁵ N₃ ]MNZ images was acquired in vitro using a steady state free precession sequence on the ¹⁵ NO₂ peak. The signal lasted over 13 min with notably long T₂ of 20.5 s. HP [¹⁵ N₃ ]MNZ was injected in the tail vein of a healthy rat, and dynamic spectroscopy was performed over the rat brain. The in vivo HP ¹⁵ N signals persisted over 70 s, demonstrating an unprecedented opportunity for in vivo studies.

Keywords: Dissolution-DNP; Hyperpolarization; Imaging Agents; NMR Spectroscopy; Nitrogen-15.