Signal Amplification in NMR and MRI using hyperpolarised compounds

Lead Research Organisation: University of York
Department Name: Chemistry

Abstract

The NMR Centre and the Neuroimaging Centre at the University of York have conducted a programme of work that has demonstrated that one of the fundamental limitations of conventional Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) techniques can be dramatically overcome. NMR is the most popular method for performing analytical and structural chemistry and MRI is the technique of choice for carrying out non-invasive imaging in humans. Even though the global markets for these techniques exceeds 6billion annually, as identified in a recent US report to Congress, both technologies are limited in application due to poor sensitivity. A process termed hyperpolarisation, developed in York throughout the last decade, allows these limitations to be overcome. We have recently shown that 0.5 seconds worth of data collection equates to 58 days on the conventional device.In laymen's terms, both NMR and MRI deal with the probing of the magnetic behaviour of nuclei within molecules. These nuclei behave like bar magnets and therefore can either have a north or south seeking orientation. Parahydrogen is simply a reaction feedstock where rather than having a mixture of such orientations, we start with a pure magnetic form. We have established a new route to utilising this feedstock in MR studies. The parahydrogen simply acts like a radiator which when brought into contact with its surroundings warms the room. In this case, the result is a potential 31,000 increase in detected signal strength. The information obtained through MIR studies is well established as providing critical information related to diagnosis and treatment in the health field. The breakthrough in sensitivity enhancement offers opportunities for a step change in modern healthcare and in high resolution NMR markets. This is achieved without the chemical modification of a material and it can employ substances that are native to the body. We therefore expect that it will not suffer from the toxicological problems associated with gadolinium contrast agents and PET and hence be well received by the medical community and laymen alike.Please see Proposal Form for details

Planned Impact

Magnetic resonance imaging (MRI) is widely and powerfully used in front-line healthcare. The importance of MRI to modern medicine is such that any advances which increase its diagnostic availability will lead to major and lasting gains, with improvements in the selectivity and the sensitivity of MRI contrast agents particularly opening up major new healthcare possibilities. Given the multidisciplinary nature of MRI, future advances will rely on teams of scientists, biomedical scientists and clinicians working closely together in an interdisciplinary manner that come from companies and Universities. Here we seek to achieve this by applying a revolutionary new technology developed at the University of York. MRI works by detecting the radio frequency signals which result from nuclei undergoing a magnetic spin state alignment change. These signals, however, are very weak, severely limiting the information available from MRI. Information enhancement can be achieved by using a contrast agent. Indeed, over 1.4 million MRI scans were performed in the NHS in 2008 where almost one third required an injected contrast agent to provide useful clinical information. The contrast agents in current widespread use are based on gadolinium. These agents are relatively sensitive giving clinician's good anatomical information, but offer no biochemical selectivity. They also suffer from potential toxicity issues. There is therefore a widely recognised and urgent need for new contrast agents and, in particular, for new agents offering significant increases in sensitivity. Increases in sensitivity will lead to major benefits in front-line healthcare which include, for example, reductions of the size of MRI scanners which in itself would greatly expand the accessibility and availability of MRI. Advances in contrast agent selectivity and specificity would also give a step change in the quality of clinically useful information available from imaging. In this context, hyperpolarised contrast agents have the potential to revolutionise magnetic resonance methods such as MRI through unrivaled gains in contrast agent sensitivity. Already, hyperpolarised xenon is used medically in lung imaging. For example, while hardware developments such as increasing magnet size in high resolution NMR spectroscopy over the last 20 years have improved the strength of the detected signal by just over one order of magnitude, hyperpolarisation can increase sensitivity by five orders of magnitude in a single step with no changes in the detection hardware. Significantly, the ability to hyperpolarise molecules of biological interest opens up the possibility of major increases in not only sensitivity both also in selectivity. It is here where York has made significant breakthroughs by utilising parahydrogen to generate hyperpolarised contrast agents simply and easily. The advantage of York's new method is that it allows the rapid production of large amounts of hyperpolarised agents without changing their molecular structure (a significant advantage over other hyperpolarisation methods and dynamic nuclear polarisation techniques where the method of contrast agent generation is limited in either amount/speed of sample and/or range of materials that can be hyperpolarised). Using the York technology, the in vivo chemical functionality of the molecule will be retained which offers the potential to create highly sensitive and highly specific contrast agents reliably and inexpensively. The benefits of the hyperpolarisation approach for improving healthcare are not restricted to imaging. In its high resolution version it enables the detailed characterisation of molecules in solution, leading to direct applications for better drug discovery product screening, sample characterisation, stability studies, and enzyme structure determinations. The impact of this methods therefore spans many areas of science, but here we seek to primarily develop the MRI context.

Publications

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Ardenkjaer-Larsen JH (2015) Facing and Overcoming Sensitivity Challenges in Biomolecular NMR Spectroscopy. in Angewandte Chemie (International ed. in English)

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Burns MJ (2015) Improving the hyperpolarization of (31)P nuclei by synthetic design. in The journal of physical chemistry. B

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Duckett SB (2013) Improving NMR and MRI sensitivity with parahydrogen. in Topics in current chemistry

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Fekete M (2015) Utilisation of water soluble iridium catalysts for signal amplification by reversible exchange. in Dalton transactions (Cambridge, England : 2003)

 
Description The work undertaken as part of this follow on fund bid allowed the ground work to be prepared to form the University spinout Hypernetics Imaging Ltd. The commerical case was developed through external consulation. We also worked towards to collection of in vivo data
Exploitation Route Our findings will be used by Hypernetics going forward.
Sectors Chemicals,Manufacturing, including Industrial Biotechology,Other

 
Description The findings of this award formed the basis to allow the University to establish a spinout. Bruker as sell a parahydrogen generator and a range of flow probes developed in part during this award.
First Year Of Impact 2013
Sector Healthcare
Impact Types Economic

 
Description GlaxoSmithKline (GSK)
Amount £65,000 (GBP)
Funding ID STU029361 
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2010 
End 09/2013
 
Description GlaxoSmithKline (GSK)
Amount £65,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2013 
End 09/2017
 
Description Wellcome Trust Capital Awards Scheme
Amount £4,360,000 (GBP)
Funding ID 092506/B/10/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2011 
End 11/2016
 
Description Wellcome Trust Strategic Awards Scheme
Amount £3,500,000 (GBP)
Funding ID 098335/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 11/2017
 
Description Bruker BioSpin 
Organisation Bruker Corporation
Department Bruker BioSpin
Country Germany 
Sector Private 
PI Contribution We have worked with Bruker to produce a parahydrogen generator, a device for the preparation of hyperpolarised samples and a flow probe for the detection of hyperpolarised signals
Collaborator Contribution Bruker have provided access to equipment and engineering. They have provided legal support for patents
Impact Bruker now sell a parahydrogen generator. A beta test version of the polariser in on test with 5 international research groups.
Start Year 2009
 
Description Using SABRE to aid in the study of biologically relevant molecules 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have worked with AstraZeneca on the application of SABRE methods to aid in the characterisation and probing of small molecules of biological relevance
Collaborator Contribution Knowledge and materials
Impact Publications
Start Year 2009
 
Description Using SABRE to aid molecular characterisation 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution GlaxoSmithKline has supported two studentships to drive forward the SABRE research. They are interested in using it to probe pharamaceutical products
Collaborator Contribution They provide knowledge and materials.
Impact Publications
Start Year 2009
 
Description Using parahydrogen to probe small molecules 
Organisation Fera Science Limited
Country United Kingdom 
Sector Public 
PI Contribution We worked with FERA to develop methods to characterise trace amounts of organic materials that are relevant to food.
Collaborator Contribution Knowledge and Materials
Impact Publicatons
Start Year 2009
 
Title Field Cycling Method for Magnetic Resonance 
Description An NMR experiment on hyperpolarizable magnetic nuclei of substrate molecules in a living human or animal body, involves polarizing the substrate molecules by non-hydrogenating para-hydrogen induced polarization (=NH-PHIP) into a singlet/pseudo singlet state in low magnetic field and injecting the substrate molecules into the living body, the body or a part thereof being previously located inside a magnet at low magnetic field. The magnet is switched on to high magnetic field, and in at least part of the substrate molecules, the singlet state/pseudo singlet state is converted into observable magnetization. An MRI or MRS measurement is carried out with the living body or the part thereof, collecting data from the substrate molecules. The NMR experiment is well applicable on hyperpolarized nuclei within a patient, with reduced losses of magnetization due to relaxation processes. 
IP Reference US8825132 
Protection Patent granted
Year Protection Granted 2014
Licensed Yes
Impact We hope that this patent will be used by Bruker BioSpin.
 
Title Hyperpolaritzation of compounds for NMR, in particular by means of PHIP 
Description An NMR method is presented having enhanced sensitivity on a compound comprising hyperpolarizable nuclei, in particular applying enhanced PHIP. Polarization is thereby transferred from a prepared fluid, which is enriched with symmetric molecules of a particular spin state (e.g. para-hydrogen enriched), directly to the hyperpolarizable nuclei of a compound, without altering the chemical identity of the compound in this process. Spin transfer is achieved using a template having sites of ordered environment, and the fluid and the compound are brought together in the presence of the template. Polarization transfer to the hyperpolarizable nuclei of the compound is thereby easier to perform and can be applied to a broader scope of compounds. 
IP Reference US8154284 
Protection Patent granted
Year Protection Granted 2012
Licensed Yes
Impact This product has been licensed to Bruker BioSpin
 
Title NMR measurement apparatus with flow-through probehead 
Description The invention relates to a device (1, 21, 31, 41, 64) for the preparation and measurement of a nuclear spin resonance (NMR) measurement sample (10), including-a flow-through NMR probehead (2), with a first tube (3) and a second tube (14) each for the supply and removal of a liquid NMR measurement sample (10),-at least one chamber (4, 22, 32) which is connected to one of the tubes (3, 14),-a sample inlet (5) for introducing the liquid measurement sample (10) into the device (1, 21, 31, 41, 64), wherein at least one chamber (4, 22, 32) has at least one connection for increasing (9, 24, 25, 42, 43, 46, 47) and releasing (8, 23, 27, 48 a , 48 b) the gas pressure, and in which at least one chamber (4, 22, 32) comprises means for mixing the liquid measurement sample (10) contained in the chamber (4, 22, 32) with a gas With the inventive device it is possible to reduce the measurement sample consumption when doing an NMR spectroscopic measurement on liquid measurement samples to which spin order can be catalytically transferred. 
IP Reference US8766631 
Protection Patent granted
Year Protection Granted 2014
Licensed Yes
Impact This has been licensed to Bruker BioSpin
 
Title Pulse sequencing with hyperpolarisable nuclei 
Description There is described a method of selective observation of non-hydrogenative para- hydrogen induced polarisation (NH-PHIP) as enhanced magnetic resonance signals which comprises separating the thermal and longitudinal spin order states. There is also described a template comprising [Ir(COD)(NHC)(Py)]+, and analogues thereof, for use in a PHIP magnetic resonance technique and a method for its preparation. 
IP Reference WO2010067076 
Protection Patent application published
Year Protection Granted 2010
Licensed Yes
Impact We are working with Bruker BipSpin on the application.
 
Title Parahydrogen Generator 
Description We worked with Bruker BioSpin to produce a device to make parahydrogen 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2013 
Impact The device is being used by a number of researchers to help support hyperpolarisation studies aligned to clinical MRI. 
URL http://www.bruker.com/products/mr/nmr/accessories/hyperpolarization/parahydrogen-generator/overview....
 
Company Name HYPERNETICS IMAGING LIMITED 
Description Currently company holds the patents associated with SABRE and seeks to develop their use. 
Year Established 2013 
Impact Currently seeking investment
 
Description 5th Australian Organometallics Meeting (Sydney) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 70 academics, postdocs and research students attended a research presentation, which sparked questions and discssion afterwards

Subsequent joint ARC grant with B Messerle (Sydney)
Year(s) Of Engagement Activity 2010
 
Description 7th Conference on Field Cycling NMR Relaxometry 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact People attended a presentation which sparked questions and discussion afterwards

Other researchers now use our methods
Year(s) Of Engagement Activity 2011
URL http://www.ffcrelax.com/ffcrelax/ffc2011/mainpage.php?folder=program&page=index.php
 
Description BioNMR workshop Weizmann Institute. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Over 50 people attended a presentation which sparked questions and discussion afterwards

Over 15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2013
URL http://www.weizmann.ac.il/weizsites/bionmr/
 
Description Chemistry Meets Imaging: Molecular Routes to Enhance Contrast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation at international meeting at Duke, USA
Year(s) Of Engagement Activity 2015
URL http://cmbi.duke.edu/conferences/
 
Description Euromar, Florence, Italy. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 100 people attended a presentation which sparked questions and discussion afterwards

Over 15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2010
URL http://www.euromar.org/about.html
 
Description Experimental Nuclear Magnetic Resonance Conference (ENC), Daytona Beach USA. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 100 people attended a presentation which sparked questions and discussion afterwards

Over 15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2010
URL http://www.enc-conference.org/
 
Description German-UK MR Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited key-note talk at international meeting.
Year(s) Of Engagement Activity 2015
URL http://www.chemie.tu-darmstadt.de/gdch-fgmr2015/fgmr_2015/index.en.jsp
 
Description Gordon Conference, In Vivo Magnetic Resonance 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 100 people attended a presentation which sparked questions and discussion afterwards

Over 15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2014
URL http://www.grc.org/programs.aspx?year=2014&program=invivo
 
Description Huddersfield Hyperpolarisation Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Series of presentations detailing aspects of hyperpolarisation
Year(s) Of Engagement Activity 2016
 
Description Imaging in 2020 VII, Bridging Molecular Imaging and Therapy, Jackson Hole USA. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact people attended a presentation which sparked questions and discussion afterwards

15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2011
 
Description Intermediary Metabolism in Cancer meeting, Dallas USA. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 100 people attended a presentation which sparked questions and discussion afterwards

Over 15 research groups worldwide have adopted our methods. This includes groups at Johns Hopkins, UT Southwestern Medical Centre, and the University Medical Center Freiburg
Year(s) Of Engagement Activity 2010
URL http://www.utsouthwestern.edu/edumedia/edufiles/departments_centers/airc/annual-symposium-202010.pdf
 
Description Invited Speaker, Euromar, Dublin, Eire. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 100 people attended a presentation which sparked questions and discussion afterwards

Over 15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2012
 
Description MRC Hyperpolarised MRI workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Workshop to consider progress in hyperpolarisation that will lead to clinical use
Year(s) Of Engagement Activity 2015
 
Description New national centre to transform medical imaging 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Detail new funding stream

A new £6.8 million research centre based across two Yorkshire universities will aim to transform diagnosis and treatment of patients suffering from cancer, heart disease and musculoskeletal diseases with the help of new medical imaging facilities to be created at Leeds Teaching Hospitals and the University of York.
Year(s) Of Engagement Activity 2014
URL http://www.york.ac.uk/news-and-events/news/2014/medical-imaging-centre/
 
Description New scanning technology aims to achieve quicker diagnosis of disease 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact New scanning technology aims to achieve quicker diagnosis of disease. Groundbreaking research taking place at the University of York could lead to Alzheimer's disease being diagnosed in minutes using a simple brain scan. Scientists are working on new technology that could revolutionise the way in which Magnetic Resonance Imaging (MRI) scans are used to view the molecular events behind diseases like Alzheimer's, without invasive procedure, by increasing the sensitivity of an average hospital scanner by 200,000 times.

The technology underpinning this project, SABRE (Signal Amplification by Reversible Exchange), has received a £3.6m Strategic Award from the Wellcome Trust to fund a team of seven post-doctoral researchers from this month.

on-going
Year(s) Of Engagement Activity 2012
URL http://www.york.ac.uk/chym/news/2012/scanning/
 
Description Opening National Centre of Hyperpolarised MRI 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Scientific talk on developments in SABRE hyperpolarisation.
Year(s) Of Engagement Activity 2016
 
Description Rank Prize Symposium 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I contributed to a workshop aimed at driving forward change in chemical detection

Over 15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2011
URL http://www.rankprize.org/index.php/symposia/general
 
Description Talk, ISMAR, Rio de Janerio, Brazil 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact people attended a presentation which sparked questions and discussion afterwards

Over 15 research groups worldwide have adopted our methods
Year(s) Of Engagement Activity 2013
 
Description Using SABRE to improve NMR and MRI 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk given in Paris
Year(s) Of Engagement Activity 2016
 
Description Wellcome Trust Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact To inform on progress towards the clinical uptake of SABRE
Year(s) Of Engagement Activity 2016
 
Description Wellcome Trust, Next Generation Brain Imaging Technologies, London, UK. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact people attended a presentation which sparked questions and discussion afterwards

Funding awarded to take methods forward.
Year(s) Of Engagement Activity 2011
 
Description York Hyperpolarisation Symposium (2 Day) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Series of 20 talks over 2 days
Year(s) Of Engagement Activity 2016
 
Description press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A press release written to share a research success

Over 30 reports in the national and international media picked up this press release. Interviews resulted on local radio.
Year(s) Of Engagement Activity 2009
URL http://www.york.ac.uk/news-and-events/news/2009/medical-diagnosis/
 
Description press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Information shared with public

Research progresses towards clinical use
Year(s) Of Engagement Activity 2010
URL http://www.york.ac.uk/news-and-events/news/2010/research/hyperpolarisation/