Composition for MRI comprising both a positive and a negative co

Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent

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424 9363, 424 9364, 514836, A61B 5055

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058690239

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BRIEF SUMMARY
The present invention relates to improvements in and relating to magnetic resonance (MR) imaging of the human or non-human animal body, in particular to a method in which positive and negative contrast agents are administered to enhance image contrast.
In MR imaging, the contrast in the image generated may be enhanced by introducing into the zone being imaged an agent (a "contrast agent"), which affects the spin reequilibration characteristics of nuclei (the "imaging nuclei" which generally are protons and more especially water protons) which are responsible for the resonance signals from which the images are generated. The enhanced contrast thus obtained enables particular organs or tissues to be visualized more clearly by increasing or by decreasing the signal level of the particular organ or tissue relative to that of its surroundings. Contrast agents raising the signal level of the target site relative to that of its surroundings are termed "positive" contrast agents whilst those lowering the signal level relative to surroundings are termed "negative" contrast agents.
The majority of materials now being proposed as MR imaging contrast agents achieve a contrast effect because they contain paramagnetic or superparamagnetic species. The use of such materials as MR contrast agents has been widely advocated and broad ranges of suitable materials have been suggested in the literature.
Thus, for example Lauterbur and others have suggested the use of manganese salts and other paramagnetic inorganic salts and complexes (see Lauterbur et al. in "Frontiers of Biological Energetics", volume 1, pages 752-759, Academic Press (1978), Lauterbur in Phil. Trans. R. Soc. Lond. B289: 483-487 (1980) and Doyle et al. in J. Comput. Assist. Tomogr. 5(2): 295-296 (1981)), Runge et al. have suggested the use of particulate gadolinium oxalate (see for example U.S. Pat. No. 4,615,879 and Radiology 147(3): 789-791 (1983)), Schering AG have suggested the use of paramagnetic metal chelates, for example of aminopolycarboxylic acids such as nitrilotriacetic acid (NTA), N,N,N'N'-ehtylenediaminetetraacetic acid (EDTA), N-hydroxyethyl-N,N'N'-ethylenediaminetriacetic acid (HEDTA), N,N,N',N",N"-diethylenetriaminepentaacetic acid (DTPA), and 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) (see for example EP-A-71564, EP-A-130934, DE-A-3401052 and U.S. Pat. No. 4,639,365), and Nycomed Imaging AS and Nycomed Salutar Inc. have suggested the use of paramagnetic metal chelates of iminodiacetic acids and other aminopolycarboxylic acids such as DTPA-BMA and DPDP (see EP-A-165728, WO-A-86/02841, EP-A-299795, EP-A-290047 and WO-A-90/08138). Besides paramagnetic metals, paramagnetic stable free radicals have also been suggested for use as positive MR imaging contrast agents (see for example EP-A-133674).
Other paramagnetic MR contrast agents are suggested or reviewed in, for example, EP-A-136812, EP-A-185899, EP-A-186947, EP-A-292689, EP-A-230893, EP-A-232751, EP-A-255471, WO-A-85/05554, WO-A-86/01112, WO-A-87/01594, WO-A-87/02893, U.S. Pat. Nos. 4,639,365, 4,687,659, 4,687,658, AJR 141: 1209-1215 (1983), Sem. Nucl. Med. 13: 364 (1983), Radiology 147: 781 (1983), J. Nucl. Med. 25: 506 (1984) and WO89/00557.
Superparamagnetic MR contrast agents (particulate negative contrast agents, e.g. sub-domain sized magnetic iron oxide particles either free or enclosed within or bound to a particle of a non-magnetic matrix material such as a polysaccharide) were disclosed by Schroder and Salford in WO-A-85/02772, by Nycomed AS in WO-A-85/04330, by Widder in U.S. Pat. No. 4,675,173, by Schering AG in DE-A-3443252 and by Advanced Magnetics Inc. in WO-A-88/00060.
While the utility of paramagnetic materials as positive MR contrast agents was recognized as early as 1978 by Lauterbur et al. (supra), the use of superparamagnetic and paramagnetic materials as negative MR contrast agents was not proposed until much later. Indeed the first paramagnetic MR contrast agents to be available commercially were positive agents such as the gadolinium chelates GdDTPA (Magnevi

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