Robust Imidazole‐15N2 Synthesis for High‐Resolution Low‐Field (0.05 T) 15N Hyperpolarized NMR Spectroscopy

Abstract

AbstractNMR 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 15N sites. Several classes of biologically relevant 15N 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 15N enrichment of imidazole‐15N2 – a promising in vivo pH sensor with pKa ∼ 7.0. A hyperpolarized 0.1 M aqueous solution (ϵ15N ∼ 146,000 fold, P15N ∼ 0.24 %) was used to record 15N NMR spectra at 0.05 T, demonstrating the feasibility of high‐resolution (full width at half maximum ∼ 1 Hz corresponding to 5 ppm 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 ∼ 30 ppm 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.