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

Efficient N-15-hyperpolarization of [N-15(3)]metronidazole was reported previously using the SignalAmplificationBy Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH)technique. This hyperpolarized FDA-approved antibiotic is a potentialcontrast agent because it can be administered in a large dose andbecause previous studies revealed long-lasting HP states with exponentialdecay constant T (1) values of up to 10 min.Possible hypoxia-sensing applications have been proposed using hyperpolarized[N-15(3)]metronidazole. In this work, we reporton the functionalization of [N-15(3)]metronidazolewith a fluorine-19 moiety via a one-step reaction to substitute the-OH group. SABRE-SHEATH hyperpolarization studies of fluoro-[N-15(3)]metronidazole revealed efficient hyperpolarizationof all three N-15 sites with maximum %P (15N) values ranging from 4.2 to 6.2%, indicating efficientspin-relayed polarization transfer in microtesla fields via the networkformed by (2) J (15N-15N).The corresponding N-15 to F-19 spin-relayed polarizationtransfer was found to be far less efficient with %P (19F) of 0.16%, i.e., more than an order of magnitude lowerthan that of N-15. Relaxation dynamics studies in microteslafields support a spin-relayed polarization transfer mechanism becauseall N-15 and F-19 spins share the same T (1) value of ca. 16-20 s and the same magneticfield profile for the SABRE-SHEATH polarization process. We envisionthe use of fluoro-[N-15(3)]metronidazole as a potentialhypoxia sensor. It is anticipated that under hypoxic conditions, thenitro group of fluoro-[N-15(3)]metronidazole undergoeselectronic stepwise reduction to an amino derivative. Ab initio calculationsof N-15 and F-19 chemical shifts of fluoro-[N-15(3)]metronidazole and its putative hypoxia-inducedmetabolites clearly indicate that the chemical shift dispersions ofall three N-15 sites and the F-19 site are largeenough to enable the envisioned hypoxia-sensing approaches.

Automated summary

Efficient hyperpolarization of [N-15(3)]metronidazole was achieved using the SABRE-SHEATH technique. The functionalization of [N-15(3)]metronidazole with a fluorine-19 moiety was also successful, resulting in efficient hyperpolarization of all three N-15 sites. The spin-relayed polarization transfer between N-15 and F-19 was found to be less efficient.