Synthetic Approaches for 15 N-Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for 15 N 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 13 C and 15 N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their long T1 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 15 N nuclei. Although large sensitivity gains are enabled by hyperpolarization, 15 N natural abundance is only ∼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 15 N-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.