Moving the goal posts: PARASHIFT proton magnetic resonance imaging

Magnetic resonance imaging (MRI) offers a window on the human body and reports the relative distribution of water in tissues within the body. MRI scans are used around the world with about 100 million examinations per year, and in 40% of these cases a contrast agent is given to the patient to assist in image clarity, aiding the radiologist in interpreting the scans observed. The scanner is tuned to the frequency at which the water hydrogen nuclei resonate, which lies in the radiofrequency range.

We propose to develop a series of safe, well tolerated contrast agents that can be observed in parallel to observation of the water signal. These contrast agents, based on rare earth metal complexes, will possess a reporting proton signal that can be observed far away from the water signal, typically at least 10 kHz away, allowing it to be selectively observed. By careful design of these systems, we will make the probe resonant frequency sensitive to local physiological parameters, such as pH or the local extracellular concentration of certain essential metal ions like magnesium and calcium. This will allow these parameters to be assessed in the region of interest that is observed. Such work is important as different regions have differing local pH gradients, and changes in extracellular calcium concentration is important in assessing bone disorders. The physiological and pathological role of magnesium is believed to be very important in stroke and ischemia, but no such real-time measurements of its levels have been made before.

A key aspect of this 'dual imaging' approach is that the new contrast agents can be detected at much lower concentration, and at levels that are safe to use. These levels lie within the current range of the approved gadolinium contrast agents that have been used clinically since 1988. This enhanced sensitivity arises from the closeness of the reporting proton signalling group to a magnetic metal centre that is incarcerated within the contrast agent. This proximity leads to enhanced sensitivity because the signal acquisition sequence can be speeded up, allowing signal intensity to be acquired about 20 times faster than would otherwise be possible.

Nationally, the project addresses the 2011 EPSRC Challenge theme, Healthcare Technologies (involving Medical Imaging and Biological Chemistry), and seeks to create impact by devising enhanced predictive/diagnostic capability by the creation of new contrast agents.

The UK used to lead the world in MRI technology, but has always lagged behind in contrast agent development. For the past 20 years, the PI has either been advising, or directly supported by, two of the European Contrast Agent/Imaging companies and so is well placed to contact Bracco spa (Milan/Ivrea) and/or Guerbet sa (Paris) to allow an assessment of the level of commercial interest in such approaches.

More recently, the PI was a major scientific adviser in the USA multi-district litigation (4 bellweather trials, involving scores of cases each, were settled out of Court in 2011/12) . The first single case to come to Court was settled on March 22 2013, in favour of Mr P Decker, $5m damages against GE Healthcare, as a result of the poor kinetic stability of acyclic gadolinium contrast agents (eg Omniscan) that had been given to patients with impaired renal failure and who subsequently developed nephrogenic systemic fibrosis. The PI has a record of assessing the impact of such work, and the need to behave cautiously when raising interest/awareness (e.g. via media releases) in considering the prospects for such work.

The project relates to the EPSRC Physical Science capability theme, notably in the direct involvement with synthetic coordination/supramolecular chemistry. Industry in the UK has strategic interests in sustaining use of MR magnet technology and image software (hardware:Oxford Instruments/ software:Siemens Molecular Imaging UK), and in promoting new chemical probe applications (e.g. GE-Amersham/ GSK). These companies will be made aware of the scientific advances defined in this work, first through the academic channels of conference dissemination and primary publications, and secondly via direct contact, provided that issues of commercial confidentiality are properly protected first. Such cases will be handled by the University's Durham Business and Innovations Service.

The PI and Co-I's will continue to cooperate with research groups around Europe (e.g. PI in ESF-COST CM 006, 2011-16; and via the European Society for Molecular Imaging) exchanging information, publicising key advances and organising short-term scientific missions of group members with selected research groups (e.g. C Faber/Munster; S. Aime/Torino) in several European countries, aided by the annual meetings of these cohorts.