Nitrogen-15 and Fluorine-19 Relaxation Dynamics and Spin-Relayed SABRE-SHEATH Hyperpolarization of Fluoro-[ 15 N 3 ]metronidazole.

Efficient 15 N-hyperpolarization of [ 15 N 3 ]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 [ 15 N 3 ]metronidazole. In this work, we report on the functionalization of [ 15 N 3 ]metronidazole with a fluorine-19 moiety via a one-step reaction to substitute the -OH group. SABRE-SHEATH hyperpolarization studies of fluoro-[ 15 N 3 ]metronidazole revealed efficient hyperpolarization of all three 15 N 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 15 N to 19 F 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 15 N. Relaxation dynamics studies in microtesla fields support a spin-relayed polarization transfer mechanism because all 15 N and 19 F 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-[ 15 N 3 ]metronidazole as a potential hypoxia sensor. It is anticipated that under hypoxic conditions, the nitro group of fluoro-[ 15 N 3 ]metronidazole undergoes electronic stepwise reduction to an amino derivative. Ab initio calculations of 15 N and 19 F chemical shifts of fluoro-[ 15 N 3 ]metronidazole and its putative hypoxia-induced metabolites clearly indicate that the chemical shift dispersions of all three 15 N sites and the 19 F site are large enough to enable the envisioned hypoxia-sensing approaches.