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

The schematic depiction of Parahydrogen Induced Polarization (PHIP) and Signal Amplification

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.


Eisenschmid TC, Kirss RU, Deutsch PP, Hommeltoft SI, Eisenberg R, Bargon J, Lawler RG, Balch AL. 1987. Para hydrogen induced polarization in hydrogenation reactions. J. Am. Chem. Soc.. 109(26):8089-8091.
Bowers CR, Weitekamp DP. Transformation of Symmetrization Order to Nuclear-Spin Magnetization by Chemical Reaction and Nuclear Magnetic Resonance. Phys. Rev. Lett.. 57(21):2645-2648.
Bowers CR, Weitekamp DP. 1987. Parahydrogen and synthesis allow dramatically enhanced nuclear alignment. J. Am. Chem. Soc.. 109(18):5541-5542.
Pravica MG, Weitekamp DP. 1988. Net NMR alignment by adiabatic transport of parahydrogen addition products to high magnetic field. Chemical Physics Letters. 145(4):255-258.
Adams RW, Aguilar JA, Atkinson KD, Cowley MJ, Elliott PIP, Duckett SB, Green GGR, Khazal IG, Lopez-Serrano J, Williamson DC. 2009. Reversible Interactions with para-Hydrogen Enhance NMR Sensitivity by Polarization Transfer. Science. 323(5922):1708-1711.
Cowley MJ, Adams RW, Atkinson KD, Cockett MCR, Duckett SB, Green GGR, Lohman JAB, Kerssebaum R, Kilgour D, Mewis RE. 2011. Iridium N-Heterocyclic Carbene Complexes as Efficient Catalysts for Magnetization Transfer frompara-Hydrogen. J. Am. Chem. Soc.. 133(16):6134-6137.
Bouchard L, Burt SR, Anwar MS, Kovtunov KV, Koptyug IV, Pines A. 2008. NMR Imaging of Catalytic Hydrogenation in Microreactors with the Use of para-Hydrogen. Science. 319(5862):442-445.
Kovtunov KV, Truong ML, Barskiy DA, Salnikov OG, Bukhtiyarov VI, Coffey AM, Waddell KW, Koptyug IV, Chekmenev EY. 2014. Propane-d6 Heterogeneously Hyperpolarized by Parahydrogen. J. Phys. Chem. C. 118(48):28234-28243.
Warren WS, Jenista E, Branca RT, Chen X. 2009. Increasing Hyperpolarized Spin Lifetimes Through True Singlet Eigenstates. Science. 323(5922):1711-1714.
Carravetta M, Levitt MH. 2004. Long-Lived Nuclear Spin States in High-Field Solution NMR. J. Am. Chem. Soc.. 126(20):6228-6229.
Kovtunov KV, Truong ML, Barskiy DA, Koptyug IV, Coffey AM, Waddell KW, Chekmenev EY. 2014. Long-Lived Spin States for Low-Field Hyperpolarized Gas MRI. Chem. Eur. J.. 20(45):14629-14632.
Reineri F, Viale A, Ellena S, Alberti D, Boi T, Giovenzana GB, Gobetto R, Premkumar SSD, Aime S. 2012. 15N Magnetic Resonance Hyperpolarization via the Reaction of Parahydrogen with 15N-Propargylcholine. J. Am. Chem. Soc.. 134(27):11146-11152.
Goldman M, Jóhannesson H, Axelsson O, Karlsson M. 2005. Hyperpolarization of 13C through order transfer from parahydrogen: A new contrast agent for MRI. Magnetic Resonance Imaging. 23(2):153-157.
Chekmenev EY, Hövener J, Norton VA, Harris K, Batchelder LS, Bhattacharya P, Ross BD, Weitekamp DP. 2008. PASADENA Hyperpolarization of Succinic Acid for MRI and NMR Spectroscopy. J. Am. Chem. Soc.. 130(13):4212-4213.
Zacharias NM, Chan HR, Sailasuta N, Ross BD, Bhattacharya P. 2012. Real-Time Molecular Imaging of Tricarboxylic Acid Cycle Metabolism in Vivo by Hyperpolarized 1-13C Diethyl Succinate. J. Am. Chem. Soc.. 134(2):934-943.
Bhattacharya P, Chekmenev EY, Reynolds WF, Wagner S, Zacharias N, Chan HR, Bünger R, Ross BD. 2011. Parahydrogen-induced polarization (PHIP) hyperpolarized MR receptor imaging in vivo: a pilot study of 13C imaging of atheroma in mice. NMR Biomed.. 24(8):1023-1028.
Shchepin RV, Coffey AM, Waddell KW, Chekmenev EY. 2014. Parahydrogen Induced Polarization of 1-13C-Phospholactate-d2 for Biomedical Imaging with >30,000,000-fold NMR Signal Enhancement in Water. Anal. Chem.. 86(12):5601-5605.
Reineri F, Boi T, Aime S. 2015. ParaHydrogen Induced Polarization of 13C carboxylate resonance in acetate and pyruvate. Nat Commun. 6(1):
Vazquez-Serrano LD, Owens BT, Buriak JM. 2006. The search for new hydrogenation catalyst motifs based on N-heterocyclic carbene ligands. Inorganica Chimica Acta. 359(9):2786-2797.
Theis T, Truong ML, Coffey AM, Shchepin RV, Waddell KW, Shi F, Goodson BM, Warren WS, Chekmenev EY. 2015. Microtesla SABRE Enables 10% Nitrogen-15 Nuclear Spin Polarization. J. Am. Chem. Soc.. 137(4):1404-1407.
Hövener J, Schwaderlapp N, Borowiak R, Lickert T, Duckett SB, Mewis RE, Adams RW, Burns MJ, Highton LAR, Green GGR, et al. 2014. Toward Biocompatible Nuclear Hyperpolarization Using Signal Amplification by Reversible Exchange: Quantitative in Situ Spectroscopy and High-Field Imaging. Anal. Chem.. 86(3):1767-1774.
Zeng H, Xu J, Gillen J, McMahon MT, Artemov D, Tyburn J, Lohman JA, Mewis RE, Atkinson KD, Green GG, et al. 2013. Optimization of SABRE for polarization of the tuberculosis drugs pyrazinamide and isoniazid. Journal of Magnetic Resonance. 23773-78.
Jiang W, Lumata L, Chen W, Zhang S, Kovacs Z, Sherry AD, Khemtong C. 2015. Hyperpolarized 15N-pyridine Derivatives as pH-Sensitive MRI Agents. Sci Rep. 5(1):
Theis T, Truong M, Coffey AM, Chekmenev EY, Warren WS. 2014. LIGHT-SABRE enables efficient in-magnet catalytic hyperpolarization. Journal of Magnetic Resonance. 24823-26.
Chekmenev, E. Y, Truong, M. L.; Coffey, A. M.; Goodson, B. M.; Shi, F.; Warren, W. S.; Theis,. 2014. T. SABRE in a Magnetic Field Shield. Provisional application filed October 29..
Gallagher FA, Kettunen MI, Day SE, Hu D, Ardenkjær-Larsen JH, Zandt Ri?, Jensen PR, Karlsson M, Golman K, Lerche MH, et al. 2008. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature. 453(7197):940-943.
Truong ML, Theis T, Coffey AM, Shchepin RV, Waddell KW, Shi F, Goodson BM, Warren WS, Chekmenev EY. 2015. 15N Hyperpolarization by Reversible Exchange Using SABRE-SHEATH. J. Phys. Chem. C. 119(16):8786-8797.
Shi F, Coffey AM, Waddell KW, Chekmenev EY, Goodson BM. 2015. Nanoscale Catalysts for NMR Signal Enhancement by Reversible Exchange. J. Phys. Chem. C. 119(13):7525-7533.
Shi F, Coffey AM, Waddell KW, Chekmenev EY, Goodson BM. 2014. Heterogeneous Solution NMR Signal Amplification by Reversible Exchange. Angew. Chem. Int. Ed.. 53(29):7495-7498.
Chekmenev, E. Y.; Goodson, B. M.; Shi, F.; Coffey, A. M. . 2014. Heterogeneous Catalysis of NMR Signal Amplification by Reversible Exchange. Vanderbilt University Reference No. VU14135, Provisional patent application filed July..
Truong ML, Shi F, He P, Yuan B, Plunkett KN, Coffey AM, Shchepin RV, Barskiy DA, Kovtunov KV, Koptyug IV, et al. 2014. Irreversible Catalyst Activation Enables Hyperpolarization and Water Solubility for NMR Signal Amplification by Reversible Exchange. J. Phys. Chem. B. 118(48):13882-13889.
Chekmenev, E. Y.; Goodson, B. M.; Truong, M. L.; Ping, H.; Best, Q.; Shi, F.; Groom, K.; Coffey, A. M.. 2014. NMR Signal Amplification by Reversible Exchange (SABRE) in Water. Vanderbilt University Reference No. VU14134, Provisional patent application filed July..

Social Media

LinkedIn icon
Twitter icon
Facebook Icon
Instagram Icon


Research. Development. Production.

We are a leading supplier to the global Life Science industry with solutions and services for research, biotechnology development and production, and pharmaceutical drug therapy development and production.

© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

Reproduction of any materials from the site is strictly forbidden without permission.