Long-lived Nuclear Hyperpolarization of Methyl Groups
Lead Research Organisation:
University of Southampton
Department Name: Sch of Chemistry
Abstract
Nuclear Magnetic Resonance (NMR) is a technique which uses the fact that the nuclei of many atoms act as tiny radiotransmitters, emitting radio signals at precisely-defined frequencies, which can be detected by a carefully-tuned detector. In an NMR experiment, the nuclei are first magnetised by placing a sample in a strong magnetic field for some time. A sequence of radiofrequency pulses is then applied to the sample, which subsequently emits radiowaves which are detected in the radio receiver. The pattern of emitted waves provides information on the chemical composition and spatial distribution of the sample.
In ordinary circumstances, the NMR and MRI signals emitted by the nuclei are relatively weak, since the magnetic moments of the nuclei point in random directions. In 2003, a revolutionary method was developed for causing the nuclei to temporarily line up with each other, increasing the strength of NMR signals by a factor of ten thousand or even more. This method is called dissolution-DNP (where DNP stands for "dynamic nuclear polarization") and an instrument to implement this is built and marketed by the British company Oxford Instruments. However a drawback of the technique is that the greatly enhanced polarization (called hyperpolarization) dies out quickly.
Our group showed in 2004 that for some substances the decay time could be extended by a factor of 10 or more by using special quantum states which are non-magnetic, called long-lived states.
Last year evidence was presented that chemical groups called methyl groups (CH3) support long-lived states. These small symmetric groups are very common in chemistry and biology. A methyl group has the shape of a small propellor and usually rotates very rapidly with respect to the rest of the molecule. Our group showed that this propellor motion gives rise to a certain class of long-lived states. We used our theory to explain some prior results that had not been explained before, and performed a first series of experiments to validate the theory.
In this project we will combine these developments to generate methyl long-lived states that are strongly hyperpolarized and give rise to greatly enhanced NMR signals. We propose methods for validating and exploiting these states in molecules containing methyl groups, which are very common in natural substances. The project involves an interdisciplinary combination of quantum mechanics, engineering, experimental spectroscopy, and chemical synthesis, all of which are essential for the success of the project. We will develop and demonstrate a range of new magnetic resonance methods with a wide range of applications in medicine, chemical engineering and materials science.
In ordinary circumstances, the NMR and MRI signals emitted by the nuclei are relatively weak, since the magnetic moments of the nuclei point in random directions. In 2003, a revolutionary method was developed for causing the nuclei to temporarily line up with each other, increasing the strength of NMR signals by a factor of ten thousand or even more. This method is called dissolution-DNP (where DNP stands for "dynamic nuclear polarization") and an instrument to implement this is built and marketed by the British company Oxford Instruments. However a drawback of the technique is that the greatly enhanced polarization (called hyperpolarization) dies out quickly.
Our group showed in 2004 that for some substances the decay time could be extended by a factor of 10 or more by using special quantum states which are non-magnetic, called long-lived states.
Last year evidence was presented that chemical groups called methyl groups (CH3) support long-lived states. These small symmetric groups are very common in chemistry and biology. A methyl group has the shape of a small propellor and usually rotates very rapidly with respect to the rest of the molecule. Our group showed that this propellor motion gives rise to a certain class of long-lived states. We used our theory to explain some prior results that had not been explained before, and performed a first series of experiments to validate the theory.
In this project we will combine these developments to generate methyl long-lived states that are strongly hyperpolarized and give rise to greatly enhanced NMR signals. We propose methods for validating and exploiting these states in molecules containing methyl groups, which are very common in natural substances. The project involves an interdisciplinary combination of quantum mechanics, engineering, experimental spectroscopy, and chemical synthesis, all of which are essential for the success of the project. We will develop and demonstrate a range of new magnetic resonance methods with a wide range of applications in medicine, chemical engineering and materials science.
Planned Impact
1. Academic impact
1.1 New knowledge and scientific advancement.
The research in this proposal is basic in nature. How are long-lived nuclear singlet states maintained in methyl groups, and how can those states be accessed? What are the best methods for polarizing such states? What are the best methods for converting the hyperpolarized methyl long-lived states into enhanced NMR signals? Can chemical reactions trigger the release of hyperpolarization from the methyl long-lived state?
In addition the proposal is highly interdisciplinary involving organic chemistry, quantum physics, image processing, and imaging.
1.2 Worldwide scientific advancement
The proposal is part of an ongoing collaboration with project partners from France.
1.3 Development of new methodologies, equipment, techniques, cross-disciplinary approaches.
The project uses new methodologies, equipment and techniques, in particular MRI and spin physics methodologies, and the development of novel hyperpolarization equipment and customised equipment/methodology for sample injection and magnetization-to-singlet conversion. The project is highly cross-disciplinary, involving organic chemistry, quantum physics, imaging, biochemistry, and reaches out into clinical medicine.
1.4 Delivering and training researchers.
Benno Meier (researcher CoI) will be given the opportunity to lead the project and to train as a research leader of the future. The careers of Giuseppe Pileio, Javier Alonso Valdesueiro and Lynda Brown will be furthered by their participation in this highly ambitious and multidisciplinary project. We will endeavour to recruit a graduate student to the project funded by other means, although this can no longer be assured due to the unwise EPSRC policy of not funding graduate students on research projects.
2. Economic and Societal Impact
2.1 Cultural. Science is a cultural activity - especially basic science. Basic research of this nature is therefore culturally enriching.
2.2 Societal benefits. The research described here is directed towards the development of enhanced imaging modalities, of potentially great benefit to the diagnosis and treatment of a wide range of diseases, especially early detection of cancer and better characterisation of its response to treatment. These new modalities can therefore considerably increase the efficacy of treatments while reducing cost.
2.3 Economic benefits. Magnet technology is a strength of UK engineering so enhancements in NMR and MRI are of long-term economic benefit to the UK. In particular Oxford Instruments has invested heavily in HYPERSENSE technology so that advances in this technology are very important for that key company. GE also has facilities located in the UK. The technologies developed in this project may underpin new startup companies.
Improved efficiency in the treatment of diseases such as stroke and cancer will reduce the cost burden on health services.
The training of researchers in advanced NMR and MRI techniques and their associated theory will equip UK industry to compete better in these areas in the future, bringing further economic benefits.
2.4 National security and social welfare. Scientific and medical improvements improve social welfare and is beneficial for national security (unlike some other common uses of government funds).
1.1 New knowledge and scientific advancement.
The research in this proposal is basic in nature. How are long-lived nuclear singlet states maintained in methyl groups, and how can those states be accessed? What are the best methods for polarizing such states? What are the best methods for converting the hyperpolarized methyl long-lived states into enhanced NMR signals? Can chemical reactions trigger the release of hyperpolarization from the methyl long-lived state?
In addition the proposal is highly interdisciplinary involving organic chemistry, quantum physics, image processing, and imaging.
1.2 Worldwide scientific advancement
The proposal is part of an ongoing collaboration with project partners from France.
1.3 Development of new methodologies, equipment, techniques, cross-disciplinary approaches.
The project uses new methodologies, equipment and techniques, in particular MRI and spin physics methodologies, and the development of novel hyperpolarization equipment and customised equipment/methodology for sample injection and magnetization-to-singlet conversion. The project is highly cross-disciplinary, involving organic chemistry, quantum physics, imaging, biochemistry, and reaches out into clinical medicine.
1.4 Delivering and training researchers.
Benno Meier (researcher CoI) will be given the opportunity to lead the project and to train as a research leader of the future. The careers of Giuseppe Pileio, Javier Alonso Valdesueiro and Lynda Brown will be furthered by their participation in this highly ambitious and multidisciplinary project. We will endeavour to recruit a graduate student to the project funded by other means, although this can no longer be assured due to the unwise EPSRC policy of not funding graduate students on research projects.
2. Economic and Societal Impact
2.1 Cultural. Science is a cultural activity - especially basic science. Basic research of this nature is therefore culturally enriching.
2.2 Societal benefits. The research described here is directed towards the development of enhanced imaging modalities, of potentially great benefit to the diagnosis and treatment of a wide range of diseases, especially early detection of cancer and better characterisation of its response to treatment. These new modalities can therefore considerably increase the efficacy of treatments while reducing cost.
2.3 Economic benefits. Magnet technology is a strength of UK engineering so enhancements in NMR and MRI are of long-term economic benefit to the UK. In particular Oxford Instruments has invested heavily in HYPERSENSE technology so that advances in this technology are very important for that key company. GE also has facilities located in the UK. The technologies developed in this project may underpin new startup companies.
Improved efficiency in the treatment of diseases such as stroke and cancer will reduce the cost burden on health services.
The training of researchers in advanced NMR and MRI techniques and their associated theory will equip UK industry to compete better in these areas in the future, bringing further economic benefits.
2.4 National security and social welfare. Scientific and medical improvements improve social welfare and is beneficial for national security (unlike some other common uses of government funds).
Organisations
- University of Southampton (Lead Research Organisation)
- Pomona College (Collaboration)
- University of Copenhagen (Collaboration)
- École Normale Supérieure, Paris (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Technical University of Denmark (Collaboration)
- Cambridge Cancer Centre (Collaboration)
- National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) (Collaboration)
- Swiss Federal Institute of Technology in Lausanne (EPFL) (Collaboration)
- University of Pennsylvania (Collaboration)
- École normale supérieure de Lyon (ENS Lyon) (Collaboration)
- University of Nottingham (Project Partner)
- University of Cambridge (Project Partner)
- French National Centre for Scientific Research (Project Partner)
Publications
Alonso-Valdesueiro J
(2018)
Testing signal enhancement mechanisms in the dissolution NMR of acetone
in Journal of Magnetic Resonance
Bengs C
(2017)
SpinDynamica: Symbolic and numerical magnetic resonance in a Mathematica environment
in Magnetic Resonance in Chemistry
Dumez JN
(2017)
Dynamic Nuclear Polarization of Long-Lived Nuclear Spin States in Methyl Groups.
in The journal of physical chemistry letters
Dumez JN
(2015)
Theory of long-lived nuclear spin states in methyl groups and quantum-rotor induced polarisation.
in The Journal of chemical physics
Eills J
(2017)
Singlet order conversion and parahydrogen-induced hyperpolarization of 13C nuclei in near-equivalent spin systems.
in Journal of magnetic resonance (San Diego, Calif. : 1997)
Eills J
(2019)
Polarization transfer via field sweeping in parahydrogen-enhanced nuclear magnetic resonance.
in The Journal of chemical physics
Elliott S
(2018)
Hyperpolarized long-lived nuclear spin states in monodeuterated methyl groups
in Physical Chemistry Chemical Physics
Elliott SJ
(2016)
Long-lived nuclear spin states in monodeuterated methyl groups.
in Physical chemistry chemical physics : PCCP
Elliott SJ
(2016)
Long-lived nuclear spin states in rapidly rotating CH2D groups.
in Journal of magnetic resonance (San Diego, Calif. : 1997)
Erriah B
(2019)
Experimental evidence for the role of paramagnetic oxygen concentration on the decay of long-lived nuclear spin order.
in RSC advances
Glöggler S
(2017)
Versatile magnetic resonance singlet tags compatible with biological conditions
in RSC Advances
Hill-Cousins JT
(2015)
Synthesis of an isotopically labeled naphthalene derivative that supports a long-lived nuclear singlet state.
in Organic letters
Kouril K
(2017)
NMR of molecular endofullerenes dissolved in a nematic liquid crystal.
in Physical chemistry chemical physics : PCCP
Kuchel P
(2015)
NMR of 133 Cs + in stretched hydrogels: One-dimensional, z - and NOESY spectra, and probing the ion's environment in erythrocytes
in Journal of Magnetic Resonance
Levitt MH
(2016)
Symmetry constraints on spin dynamics: Application to hyperpolarized NMR.
in Journal of magnetic resonance (San Diego, Calif. : 1997)
Ogba OM
(2017)
Origins of Small Proton Chemical Shift Differences in Monodeuterated Methyl Groups.
in The Journal of organic chemistry
Pileio G
(2017)
Singlet NMR methodology in two-spin-1/2 systems.
in Progress in nuclear magnetic resonance spectroscopy
Ripka B
(2018)
Hyperpolarized fumarate via parahydrogen.
in Chemical communications (Cambridge, England)
Roy SS
(2015)
Enhancement of quantum rotor NMR signals by frequency-selective pulses.
in Journal of magnetic resonance (San Diego, Calif. : 1997)
Sheberstov KF
(2019)
Excitation of singlet-triplet coherences in pairs of nearly-equivalent spins.
in Physical chemistry chemical physics : PCCP
Stevanato G
(2017)
Alternating Delays Achieve Polarization Transfer (ADAPT) to heteronuclei in PHIP experiments
in Journal of Magnetic Resonance
Stevanato G
(2015)
Long-lived nuclear spin states far from magnetic equivalence.
in Physical chemistry chemical physics : PCCP
Stevanato G
(2015)
A nuclear singlet lifetime of more than one hour in room-temperature solution.
in Angewandte Chemie (International ed. in English)
Utz M
(2015)
Visualisation of quantum evolution in the Stern-Gerlach and Rabi experiments.
in Physical chemistry chemical physics : PCCP
Webb W
(2020)
The Significance of Metal Coordination in Imidazole-Functionalized Metal-Organic Frameworks for Carbon Dioxide Utilization
in Chemistry - A European Journal
Description | Methyl groups support long-lived states. |
Exploitation Route | Enhanced NMR and MRI |
Sectors | Chemicals Healthcare Pharmaceuticals and Medical Biotechnology |
Description | EPSRC Platform Grant |
Amount | £1,784,689 (GBP) |
Funding ID | EP/P009980/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 02/2022 |
Description | European Research Council Advanced Grant |
Amount | € 2,762,223 (EUR) |
Funding ID | 786707 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 09/2018 |
End | 09/2023 |
Description | Underpinning Equipment |
Amount | £1,999,999 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2018 |
Title | Bullet-DNP equipment |
Description | Device and control system for rapid dissolution of a solid polarized by dynamic nuclear polarization |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Research insights and advances |
Title | Cryogenic NMR probe |
Description | Equipment for performing NMR at cryogenic temperatures |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2015 |
Provided To Others? | No |
Impact | Advances in scientific understanding from measurement results |
Title | SpinDynamica software |
Description | SpinDynamica software is a Mathematica-based system for analyzing, understanding, and simulating nuclear spin dynamics, with applications to NMR and MRI. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Widespread use in the NMR community |
URL | http://www.spindynamica.soton.ac.uk/ |
Title | Dataset for: SpinDynamica: Symbolic and numerical magnetic resonance in a Mathematica environment |
Description | SpinDynamica is a set of Mathematica packages for performing numerical and symbolic analysis of a wide range of magnetic resonance experiments and phenomena. An overview of the SpinDynamica architecture and functionality is given, with some simple representative examples. |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
URL | https://wiley.figshare.com/articles/dataset/Dataset_for_SpinDynamica_Symbolic_and_numerical_magnetic... |
Title | Dataset for: SpinDynamica: Symbolic and numerical magnetic resonance in a Mathematica environment |
Description | SpinDynamica is a set of Mathematica packages for performing numerical and symbolic analysis of a wide range of magnetic resonance experiments and phenomena. An overview of the SpinDynamica architecture and functionality is given, with some simple representative examples. |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Widely used worldwide for the analysis and understanding of nuclear magnetic resonance |
URL | https://wiley.figshare.com/articles/dataset/Dataset_for_SpinDynamica_Symbolic_and_numerical_magnetic... |
Description | CH2D collaboration |
Organisation | National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) |
Country | France |
Sector | Academic/University |
PI Contribution | NMR theory, measurements and methodology |
Collaborator Contribution | NMR theory, measurements and methodology. Quantum chemistry collaborations. |
Impact | see grant entries. |
Start Year | 2016 |
Description | CH2D collaboration |
Organisation | Pomona College |
Country | United States |
Sector | Academic/University |
PI Contribution | NMR theory, measurements and methodology |
Collaborator Contribution | NMR theory, measurements and methodology. Quantum chemistry collaborations. |
Impact | see grant entries. |
Start Year | 2016 |
Description | Hyperpolarization collaboration |
Organisation | Cambridge Cancer Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | NMR techniques, materials, theory, simulations |
Collaborator Contribution | MRI techniques, materials, methodology |
Impact | Too complex to report here. |
Start Year | 2010 |
Description | Hyperpolarization collaboration |
Organisation | Swiss Federal Institute of Technology in Lausanne (EPFL) |
Country | Switzerland |
Sector | Public |
PI Contribution | NMR techniques, materials, theory, simulations |
Collaborator Contribution | MRI techniques, materials, methodology |
Impact | Too complex to report here. |
Start Year | 2010 |
Description | Hyperpolarization collaboration |
Organisation | University of Copenhagen |
Country | Denmark |
Sector | Academic/University |
PI Contribution | NMR techniques, materials, theory, simulations |
Collaborator Contribution | MRI techniques, materials, methodology |
Impact | Too complex to report here. |
Start Year | 2010 |
Description | Hyperpolarization collaboration |
Organisation | University of Pennsylvania |
Country | United States |
Sector | Academic/University |
PI Contribution | NMR techniques, materials, theory, simulations |
Collaborator Contribution | MRI techniques, materials, methodology |
Impact | Too complex to report here. |
Start Year | 2010 |
Description | Hyperpolarization collaboration |
Organisation | École normale supérieure de Lyon (ENS Lyon) |
Country | France |
Sector | Academic/University |
PI Contribution | NMR techniques, materials, theory, simulations |
Collaborator Contribution | MRI techniques, materials, methodology |
Impact | Too complex to report here. |
Start Year | 2010 |
Description | dDNP collaboration |
Organisation | Technical University of Denmark |
Country | Denmark |
Sector | Academic/University |
PI Contribution | NMR methodology, theory and experiments. |
Collaborator Contribution | NMR methodology, theory and experiments. |
Impact | see grant entries. |
Start Year | 2016 |
Description | dDNP collaboration |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | NMR methodology, theory and experiments. |
Collaborator Contribution | NMR methodology, theory and experiments. |
Impact | see grant entries. |
Start Year | 2016 |
Description | dDNP collaboration |
Organisation | École Normale Supérieure, Paris |
Country | France |
Sector | Academic/University |
PI Contribution | NMR methodology, theory and experiments. |
Collaborator Contribution | NMR methodology, theory and experiments. |
Impact | see grant entries. |
Start Year | 2016 |
Description | dDNP collaboration |
Organisation | École normale supérieure de Lyon (ENS Lyon) |
Country | France |
Sector | Academic/University |
PI Contribution | NMR methodology, theory and experiments. |
Collaborator Contribution | NMR methodology, theory and experiments. |
Impact | see grant entries. |
Start Year | 2016 |
Title | SpinDynamica |
Description | Large set of Mathematica packages for analyzing, simulating, and understanding NMR experiments. |
Type Of Technology | Software |
Year Produced | 2017 |
Impact | widely used in NMR community |
URL | http://www.spindynamica.soton.ac.uk |