Parahydrogen Induced Polarization

Parahydrogen Induced Polarization (PHIP)¹ is a hyperpolarization technique, where the nuclear singlet state of parahydrogen is utilized as a source of hyperpolarization.² Unlike most other hyperpolarization techniques, where nuclear spin polarization (P) is slowly built up by polarization transfer from other highly polarized species (i.e. most frequently electrons as in case of dissolution Dynamic Nuclear Polarization (d-DNP) and Spin Exchange Optical Pumping (SEOP) techniques), PHIP allows for preparation of hyperpolarized contrast agents in seconds after chemical reaction of unsaturated molecular precursor with parahydrogen molecule (hydrogenative PHIP via PASADENA³ or ALTADENA⁴ conditions) or using the exchange process (non-hydrogenative PHIP where the to-be-hyperpolarized substrate and parahydrogen exchange on the same metal center) via Signal Amplification by Reversible Exchange (SABRE)^5-6 process.

The goal of hydrogenative PHIP is to break the magnetic symmetry of nascent parahydrogen protons after the addition process, making these protons effectively hyperpolarized, Figure 1A. While in principle hyperpolarized protons sites can be used directly for imaging applications,^7-8 the spin lattice relaxation time of hyperpolarized protons is frequently too short for biomedical use (unless long-lived spin states^9-10 are created¹¹), and polarization from nascent parahydrogen protons can be transferred intramolecularly to longer-lived ¹³C¹² and ¹⁵N¹³ spins using spin-spin couplings.^{12, 14} A number of compounds were efficiently (P > 10%) hyperpolarized in large quantity and concentration to prepare sufficiently large payload of hyperpolarized contrast agent to interrogate in vivo metabolic processes including 2-hydroxyethyl propionate (HEP) for angiography,¹⁵ succinate¹⁶ for Krebs cycle imaging,¹⁷ tetrafluoropropyl propionate (TFPP) for plaque imaging.¹⁸ Other emerging PHIP based hyperpolarized contrast agents include phospholactate (PLAC),¹⁹ and ¹³C-pyruvate and ¹³C-acetate esters.²⁰

The goal of non-hydrogenative SABRE hyperpolarization technique is to perform a simultaneous exchange of parahydrogen and to-be-hyperpolarized compound on the same metal center (frequently hexacoordinate Iridium complex^{6, 21}) on the time scale inversely proportional to the spin-spin coupling interaction between metal hydride proton spins (source of hyperpolarization) and the target nucleus on the exchangeable agent, Figure 1B. Efficient direct SABRE hyperpolarization (P ~ 10%) has been demonstrated for proton sites⁶ as well as longer-lived ¹⁵N sites²² in exchangeable N-heterocyclic compounds (e.g. pyridine and nicotinamide) using the corresponding matching low magnetic field corresponding to homonuclear (i.e. proton-to-proton transfer) or heteronuclear (i.e. proton-to-nitrogen transfer) SABRE conditions respectively. While a few promising biomolecules have been successfully hyperpolarized with sufficiently large payload of proton hyperpolarization: e.g. nicotinamide,^{5, 23} tuberculosis drugs pyrazinamide and isoniazid,²⁴ their in vivo proton spin-lattice relaxation T₁ is known to be relatively low, causing short in vivo lifetime of hyperpolarized spin states, and no in vivo applications have been demonstrated to date as of April 2015. On the other hand, ¹⁵N sites of pyridine-based and other N-heterocycles²⁵ amenable to ¹⁵N SABRE hyperpolarization^{22, 26-27} can act as useful contrast agents for pH imaging.²⁵ Non-invasive in vivo pH sensing is important metabolic readout especially relevant in the context of cancer (tumors are known to be acidic), which has already been shown useful in the context of d-DNP hyperpolarized ¹³C-bicarbonate pH imaging.²⁸ Therefore, ¹⁵N pH imaging will likely result in one of the first in vivo applications of SABRE hyperpolarization technique,²⁹ especially when taking advantage of recent developments in SABRE hyperpolarization using recyclable³⁰ heterogeneous catalysts^31-32 and SABRE in aqueous medium.^33-34