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Parahydrogen Induced Polarization


Eduard Y. Chekmenev
Vanderbilt University Institute of Imaging Science (VUIIS),
Department of Radiology, Department of Biomedical Engineering,
Department of Biochemistry, Vanderbilt-Ingram Cancer
Center (VICC), Nashville, Tennessee, 37232-2310, United States


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 states9-10 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 complex6, 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 hyperpolarization22, 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 catalysts31-32 and SABRE in aqueous medium.33-34


Figure 1. The schematic depiction of Parahydrogen Induced Polarization (PHIP) and Signal Amplification by Reversible Exchange (SABRE) hyperpolarization techniques. A) PHIP requires hydrogenation via pairwise addition of parahydrogen via PASADENA3 or ALTADENA4 methods. Once the symmetry of parahydrogen singlet state is broken, near unity nuclear spin polarization is realized on nascent parahydrogen protons, which can be used directly (e.g. hyperpolarized propane-d6 gas8) or (A) SABRE5 being non-hydrogenative method requires chemical exchange of parahydrogen and to-be-hyperpolarized contrast agent on metal (frequently Iridium hexacoordinate IMes21 complex) catalyst.



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  22. Theis, T.; Truong, M. L.; Coffey, A. M.; Shchepin, R. V.; Waddell, K. W.; Shi, F.; Goodson, B. M.; Warren, W. S.; Chekmenev, E. Y. Microtesla SABRE Enables 10% Nitrogen-15 Nuclear Spin Polarization. J. Am. Chem. Soc. 2015, 137, 1404-1407.
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  27. Chekmenev, E. Y.; Truong, M. L.; Coffey, A. M.; Goodson, B. M.; Shi, F.; Warren, W. S.; Theis, T. SABRE in a Magnetic Field Shield. Provisional application filed October 29, 2014.
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  29. Truong, M. L.; Theis, T.; Coffey, A. M.; Shchepin, R. V.; Waddell, K. W.; Shi, F.; Goodson, B. M.; Warren, W. S.; Chekmenev, E. Y. 15N Hyperpolarization By Reversible Exchange Using SABRE-SHEATH. J. Phys. Chem. C 2015, DOI 10.1021/acs.jpcc.5b01799.
  30. Shi, F.; Coffey, A. M.; Waddell, K. W.; Chekmenev, E. Y.; Goodson, B. M. Nanoscale Catalysts for NMR Signal Enhancement by Reversible Exchange. J. Phys. Chem. C 2015, DOI: 10.1021/acs.jpcc.5b02036.
  31. Shi, F.; Coffey, A. M.; Waddell, K. W.; Chekmenev, E. Y.; Goodson, B. M. Heterogeneous Solution NMR Signal Amplification by Reversible Exchange. Angew. Chem. Int. Ed. 2014, 53, 7495–7498.
  32. Chekmenev, E. Y.; Goodson, B. M.; Shi, F.; Coffey, A. M. Heterogeneous Catalysis of NMR Signal Amplification by Reversible Exchange. Vanderbilt University Reference No. VU14135, Provisional patent application filed July, 2014.
  33. Truong, M. L.; Shi, F.; He, P.; Yuan, B.; Plunkett, K. N.; Coffey, A. M.; Shchepin, R. V.; Barskiy, D. A.; Kovtunov, K. V.; Koptyug, I. V.; Waddell, K. W.; Goodson, B. M.; Chekmenev, E. Y. Irreversible Catalyst Activation Enables Hyperpolarization and Water Solubility for NMR Signal Amplification by Re-versible Exchange. J. Phys. Chem. B 2014, 18 13882–13889.
  34. Chekmenev, E. Y.; Goodson, B. M.; Truong, M. L.; Ping, H.; Best, Q.; Shi, F.; Groom, K.; Coffey, A. M. NMR Signal Amplification by Reversible Exchange (SABRE) in Water. Vanderbilt University Reference No. VU14134, Provisional patent application filed July, 2014.