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

Abstract

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

15N Hyperpolarization of Metronidazole Antibiotic in Aqueous Media Using Phase-Separated Signal Amplification by Reversible Exchange with Parahydrogen

“…35−42 Indeed, computational studies revealed the feasibility of employing HP uniformly 15 Nlabeled metronidazole ([ 15 N 3 ]metronidazole) for hypoxia sensing applications. 43 Moreover, pilot 15 N d-DNP studies using HP [ 15 N 3 ]metronidazole revealed the feasibility of in vivo utilization of HP [ 15 N 3 ]metronidazole in healthy rats. 43 These developments make HP nitroimidazoles in general and HP [ 15 N 3 ]metronidazole in particular promising magnetic resonance sensors with diagnostic specificity to tumor hypoxia.…”

“…43 Moreover, pilot 15 N d-DNP studies using HP [ 15 N 3 ]metronidazole revealed the feasibility of in vivo utilization of HP [ 15 N 3 ]metronidazole in healthy rats. 43 These developments make HP nitroimidazoles in general and HP [ 15 N 3 ]metronidazole in particular promising magnetic resonance sensors with diagnostic specificity to tumor hypoxia. 33 It was shown previously that [ 15 N 3 ]metronidazole can be successfully hyperpolarized in deuterated methanol via SABRE-SHEATH with P 15N of ∼16% for the 15 NO 2 group.…”