Nitrogen-15 and Fluorine-19 Relaxation Dynamics and Spin-Relayed SABRE-SHEATH Hyperpolarization of Fluoro-[N]metronidazole.

Efficient N-hyperpolarization of [N]metronidazole was reported previously using the Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) technique. This hyperpolarized FDA-approved antibiotic is a potential contrast agent because it can be administered in a large dose and because previous studies revealed long-lasting HP states with exponential decay constant values of up to 10 min. Possible hypoxia-sensing applications have been proposed using hyperpolarized [N]metronidazole. In this work, we report on the functionalization of [N]metronidazole with a fluorine-19 moiety via a one-step reaction to substitute the -OH group. SABRE-SHEATH hyperpolarization studies of fluoro-[N]metronidazole revealed efficient hyperpolarization of all three N sites with maximum % values ranging from 4.2 to 6.2%, indicating efficient spin-relayed polarization transfer in microtesla fields via the network formed by . The corresponding N to F spin-relayed polarization transfer was found to be far less efficient with % of 0.16%, i.e., more than an order of magnitude lower than that of N. Relaxation dynamics studies in microtesla fields support a spin-relayed polarization transfer mechanism because all N and F spins share the same value of ca. 16-20 s and the same magnetic field profile for the SABRE-SHEATH polarization process. We envision the use of fluoro-[N]metronidazole as a potential hypoxia sensor. It is anticipated that under hypoxic conditions, the nitro group of fluoro-[N]metronidazole undergoes electronic stepwise reduction to an amino derivative. Ab initio calculations of N and F chemical shifts of fluoro-[N]metronidazole and its putative hypoxia-induced metabolites clearly indicate that the chemical shift dispersions of all three N sites and the F site are large enough to enable the envisioned hypoxia-sensing approaches.