Triple Imaging with PARASHIFT Probes

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Magnetic resonance imaging (MRI) affords a window to the human body reporting the relative distribution of water in tissues within the body. MRI scans are used for clinical diagnosis with 100 million examinations per year, wherein 40% use a contrast agent that is given to the patient to enhance image clarity, aiding the radiologist in interpreting the scans observed. The scanner is tuned to the frequency where the water hydrogen nuclei resonate. This lies in the radiofrequency range. We will develop a series of contrast agents that can be simultaneously observed with the water signal. These contrast agents, based on rare earth metal complexes, possess an intense reporting proton signal that can be observed far away from the water signal, typically 10 to 20 kHz away, allowing their selective observation. By carefully designing their molecular structure , the probe resonant frequency can be made to be sensitive not only to local temperature but also to other physiological parameters, such as pH or the local extracellular concentration of sodium. By administering at the same time, two rare earth complexes with different metals (such as thulium/dysprosium or erbium/terbium), each probe localises to the same region of the body and their shifted signals can be observed simultaneously with the water signal. This is termed a triple imaging experiment, and by measuring the two probe frequencies in, for example, the liver or the kidney, both the temperature and the pH can be assessed in the region of interest that is studied. In general, local temperature increases in the liver or kidney are indicators of disease, especially inflammation, as occurs in hepatitis or fibrosis of the liver. Similarly, altered extracellular pH is indicative of tissue ischaemia as occurs in many diseases where blood flow has been restricted , e.g. coronary heart disease and end stage renal disease. A key aspect of this 'triple imaging' approach is that the new contrast agents can be detected at relatively low concentration, and at levels that are safe to use. These levels lie within the current range of the approved gadolinium contrast agents based on a cyclic ring structure 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: the signal acquisition sequence can be speeded up, allowing signal intensity to be acquired about 20 times faster than otherwise possible.