Heteronuclear Parahydrogen-Induced Hyperpolarization via Side Arm Hydrogenation

Abstract

Nuclear spin hyperpolarization dramatically enhances the sensitivity of nuclear magnetic resonance spectroscopy and imaging. Hyperpolarization of biomolecules (e.g., pyruvate) is of particular interest as it allows one to follow their metabolism, providing a diagnostic tool for various pathologies, including cancer. In this regard, the hyperpolarization of 13C nuclei is especially beneficial due to its typically relatively long hyperpolarization lifetime and the absence of a background signal. Parahydrogen-induced polarization (PHIP) is arguably the most affordable hyperpolarization technique. PHIP exploits the pairwise addition of parahydrogen to an unsaturated substrate. This sets limitations on the range of compounds amenable to direct PHIP hyperpolarization. The range of molecules that can be hyperpolarized with PHIP significantly expanded in 2015 when PHIP by means of side arm hydrogenation (PHIP-SAH) was introduced. Herein, parahydrogen is added to an unsaturated alcoholic moiety of an ester followed by polarization transfer to carboxylate 13C nuclei with a subsequent side arm cleavage. In this review, the recent advances in PHIP-SAH are discussed, including the synthetic methodology to produce isotopically labeled precursors, peculiarities of pairwise addition of parahydrogen to PHIP-SAH precursors, polarization transfer approaches, hyperpolarization lifetime, side arm cleavage, purification of hyperpolarized solution, and, finally, in vitro and in vivo applications.