New methods to strengthen NMR signals
Stronger alignment of atomic nuclei in Nuclear Magnetic Resonance (NMR) would enable significantly more detailed MRI scans. We spoke to Professor Malcolm Levitt, Bonifac Legrady and Mohamed Sabba about how they generated hyperpolarised nuclear states which provide a very strong NMR signal, how they plan to maintain the hyperpolarised states for a long time under ambient conditions, and the wider implications of their research.
The properties of atomic nuclei are the basis of nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI), which is an important tool in diagnosis and in monitoring the effectiveness of medical treatment. Atomic nuclei have a property called spin which causes them to be slightly magnetic. The magnetic nuclei align very weakly when placed in the strong magnetic field of an MRI scanner, which then detects changes in those nuclei when a radiofrequency field is turned on and off.
“Around 1 in 100,000 atomic nuclei are aligned properly. Although that alignment is very small, it is still enough to perform NMR experiments and MRI,” outlines Malcolm Levitt, Professor of Chemistry at the University of Southampton in the UK. Stronger alignment of these atomic nuclei would lead to correspondingly stronger NMR signals, which would provide more information about internal structures within the body. “Currently MRI only detects how many hydrogen nuclei – protons – there are in a particular pixel. It can’t tell you which chemical substances are there,” explains Professor Levitt. “If the NMR signal was stronger, and lasted longer, then we would be able to get signals from individual chemicals.” Furthermore, if the strong nuclear alignment could be maintained for long enough, it would allow us to follow chemical reactions and metabolism, happening within the body.
Hyperpolarisation techniques
A number of hyperpolarisation techniques are available which lead to much stronger polarisation of atomic nuclei, essentially
increasing the number which are properly aligned. These hyperpolarised NMR signals have been used in MRI, yet the effect only lasts for a relatively short time, an issue that Professor Levitt and his colleagues in the FunMagResBeacons research project are addressing. “We are working with some phenomena we’ve discovered, in which the polarisation lasts for much longer,” he says. Several candidate molecules have been identified, one of which is a tworing structure called naphthalene, which has been modified for the project. “Our colleagues have produced this molecule with two 13C nuclei. We’re interested in this system because the techniques that we’ve been using are capable of aligning the two nuclear spins of the 13C nuclei such that they are opposite to each other,” continues Professor Levitt. “We’ve been able to show that this type of polarisation, which we call singlet order, can last for up to an hour, as
opposed to just a few seconds. Researchers in the project have taken this system to our collaborators in Lyon and performed some hyperpolarisation experiments.”
This research involves using a technique called dynamic nuclear polarisation (DNP) to generate hyperpolarised nuclear states, providing a very strong NMR signal. “We can follow how these quantum states evolve over time,” says Bonifac Legrady, a researcher also working on the FunMagResBeacons project. Whereas traditional triplet spin states decay in just a few seconds, these special singlet states produced by DNP last around 25 times longer, opening up the possibility of eventually using similar molecules as beacons in the body and enabling clinicians to follow processes over sustained periods of time.
“We could hyperpolarise a substance, store a state, and then introduce that into the human body. Then with a switch we could switch these small magnetic resonance beacons on.
Molecular structure of the compound studied. At the junction of the aromatic rings, two 13C isotopes were synthetically introduced. These nuclei form a spin system that can support various spin states, such as those associated with singlet and triplet polarisation.
We get a big flash, and we can track them in space,” explains Legrady. “We’ve been working on a switch, activated by a special sequence of radiofrequency magnetic fields, to convert the traditional triplet states into the special singlet state, exchanging the bright beacons and the dim beacons, and are also investigating other functionalities.”
A specific sequence of magnetic fields is used to effectively get at the stored polarisation. The molecule itself is designed in such a way that in order to put the polarisation in - and take it out again - a particular radiofrequency pulse sequence with certain timings has to be applied, which Professor Levitt says acts a bit like a key.
“You need everything in just the right place to open the lock and get at the polarisation,” he says. The focus in this work is still on developing the underlying methodology, with more still to be done before these molecules can be applied
future and develop the technology further. A lot of progress has been made over the course of the project in developing the methodology and theory around the switch, providing sound foundations for continued development. “An analogy can be drawn here with paramagnetic relaxation, a phenomenon which has been known about in NMR since the ‘40s. There had been decades of research developing the theory of paramagnetic relaxation,” says Mohamed Sabba, a researcher working on the project. This work led on to the development of new contrast agents, which are used today in hospitals across the world, now researchers aim to develop the theory and methodology around these innovative molecular agents.
“Although we’re developing the underpinning methodology around this, we’re a long way from actually using these agents in MRI,” stresses Professor Levitt.
“Currently MRI only detects how many hydrogen nuclei there are in a particular pixel, it can’t tell you which chemical substances are there. If the NMR signal was stronger, and lasted longer, then we would be able to get signals from individual chemicals, and image the progress of their chemical reactions.”
in MRI, while the project’s research also holds relevance to other fields. “We’re manipulating quantum objects called spins, and generating particular states, which are coupled together. This is a topic of interest not just in NMR and MRI, but also in other fields. For example, these types of manipulations are also used in quantum information processing and quantum computing,” continues Professor Levitt. “There is interest in using these long-lived singlet states as a sort of register in quantum computing. So our research holds relevance to the general area of quantum technologies.”
The FunMagResBeacons project itself is set to conclude later this year, yet Professor Levitt plans to continue his research in this area in
Researchers are currently working to bring together and publish the results that have been obtained so far, which can then provide a strong basis for further grant applications. This research is also having a wider impact, with the project’s findings filtering into the work of other groups. “Some of the research that has been conducted as part of this project has spun offin some cases by other groups - into other areas which we didn’t really anticipate at the outset, and which are not directly related to what we have done,” continues Professor Levitt. “This is part of how the scientific dissemination process works. You develop a new type of tool, then somebody else comes along and sees that it is very useful for what they want to do.”
FunMagResBeacons
Functionalised Magnetic Resonance Beacons for Enhanced Spectroscopy and Imaging
Project Objectives
The FunMagResBeacons project designs molecules which can sustain a high degree of nuclear magnetic order for an extended time interval, prepares these molecules in a low-entropy hyperpolarised state, and uses sequences of magnetic fields to release the nuclear spin order in the form of strong and informative radio signals.
Project Funding
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant agreement ID: 786707.
Contact Details
Project Coordinator, Malcolm Levitt School of Chemistry Room 27:2026
University of Southampton Southampton SO17 1BJ England
E: mhl@soton.ac.uk
W: https://www.hmrlab.eu/ W: https://www.southampton.ac.uk/ research/projects/functionalized-magneticresonance-beacons-for-enhancedspectroscopy-imaging
Malcolm Levitt has been a Professor in Physical Chemistry at the University of Southampton, UK, since 2001. His main interests are the theory and methodology of nuclear magnetic resonance (NMR), as well as spectroscopic and theoretical investigations of molecules conned to small cavities. His main research themes within NMR include the use of symmetry to control dissipation, and hyperpolarization techniques for the enhancement of NMR signals.
Sami Jannin has been a Professor at the Claude Bernard Lyon 1 University, France, since 2016. He is currently the leader of the Hyperpolarized Magnetic Resonance team at the High Field NMR Center in Lyon. His main research interests are the development of breakthrough instrumentation, methods, and applications in hyperpolarized magnetic resonance.
