Nitrogen-15 and Fluorine-19 Relaxation Dynamics and Spin-Relayed SABRE-SHEATH Hyperpolarization of Fluoro‑[15N3]metronidazole

Efficient 15N-hyperpolarization of [15N3]­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 T 1 values of up to 10 min. Possible hypoxia-sensing applications have been proposed using hyperpolarized [15N3]­metronidazole. In this work, we report on the functionalization of [15N3]­metronidazole with a fluorine-19 moiety via a one-step reaction to substitute the −OH group. SABRE-SHEATH hyperpolarization studies of fluoro-[15N3]­metronidazole revealed efficient hyperpolarization of all three 15N sites with maximum %P 15N values ranging from 4.2 to 6.2%, indicating efficient spin-relayed polarization transfer in microtesla fields via the network formed by 2 J 15N‑15N. The corresponding 15N to 19F spin-relayed polarization transfer was found to be far less efficient with %P 19F of 0.16%, i.e., more than an order of magnitude lower than that of 15N. Relaxation dynamics studies in microtesla fields support a spin-relayed polarization transfer mechanism because all 15N and 19F spins share the same T 1 value of ca. 16–20 s and the same magnetic field profile for the SABRE-SHEATH polarization process. We envision the use of fluoro-[15N3]­metronidazole as a potential hypoxia sensor. It is anticipated that under hypoxic conditions, the nitro group of fluoro-[15N3]­metronidazole undergoes electronic stepwise reduction to an amino derivative. Ab initio calculations of 15N and 19F chemical shifts of fluoro-[15N3]­metronidazole and its putative hypoxia-induced metabolites clearly indicate that the chemical shift dispersions of all three 15N sites and the 19F site are large enough to enable the envisioned hypoxia-sensing approaches.