Synthetic Approaches for 15N-Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for 15N NMR Signal Amplification by Reversible Exchange in Microtesla Magnetic Fields

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by using high-resolution NMR spectroscopy to real-time metabolic imaging in vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the C-13 and N-15 sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their long T-1 allows hyperpolarized states to be retained for up to tens of minutes. Signal amplification by reversible exchange (SABRE) is a low-cost and ultrafast hyperpolarization technique that has been shown to be versatile for the hyperpolarization of N-15 nuclei. Although large sensitivity gains are enabled by hyperpolarization, N-15 natural abundance is only similar to 0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of N-15-labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through spontaneous polarization transfer from parahydrogen. Also, these principles can certainly be applied for hyperpolarization of these emerging contrast agents using dynamic nuclear polarization and other techniques.

Automated summary

NMR hyperpolarization techniques greatly increase nuclear spin polarization, leading to significant sensitivity gains for applications in high-resolution NMR spectroscopy and real-time metabolic imaging. Various hyperpolarization techniques exist, with a focus on targeting C-13 and N-15 sites in biocompatible agents. Long T-1 values of these sites allow hyperpolarized states to be retained for extended periods, with SABRE being a versatile low-cost technique for hyperpolarization of N-15 nuclei.