Robust Imidazole-15N2 Synthesis for High-Resolution Low-Field (0.05 T) 15NHyperpolarized NMR Spectroscopy

NMR hyperpolarization techniques have the potential to revolutionize the field of NMR spectroscopy and molecular MRI because they can transiently enhance nuclear spin polarization by 4-8 orders of magnitude, with corresponding gains in NMR signal-to-noise ratio (SNR). The SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei) technique, first demonstrated in 2015, allows for direct, efficient (>20% nuclear spin polarization), and fast (in under one minute) hyperpolarization of N-15 sites. Several classes of biologically relevant N-15 hyperpolarized contrast agents have been efficiently hyperpolarized to date including pH sensors, which can be potentially useful for non-invasive pH imaging of cancer and other diseases with altered metabolism. Here, we report the optimized N-15 enrichment of imidazole-N-15(2) - a promising invivo pH sensor with pKa similar to 7.0. A hyperpolarized 0.1M aqueous solution (epsilon(15N) similar to 146,000 fold, P-15N similar to 0.24%) was used to record (NNMR)-N-15 spectra at 0.05 T, demonstrating the feasibility of high-resolution (full width at half maximum similar to 1Hz corresponding to 5ppm at 0.05 T) NMR spectroscopy near its pKa (7.0) at ultra-low magnetic field. Given that proton-binding events modulate the chemical shift by similar to 30ppm for this pH-sensing probe, our results demonstrate the feasibility of ultra-low-field pH sensing near its pKa (7.0) with SNR approaching that of high-field (9.4 T) MR.