Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1991-12-10
1993-09-07
Robinson, Allen J.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 4, 424 5, 436173, 436806, 1286534, 514184, 514492, 514836, 534 16, G01N 2408, G01N 2304, A61K 31555
Patent
active
052426831
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to improvements in and relating to contrast media for use in diagnostic imaging, and especially to contrast media suitable for imaging the gastrointestinal (GI) tract.
In X-ray imaging and magnetic resonance imaging (MRI), contrast agents may be administered to the patient in order to enhance image contrast between regions into which the contrast agent distributes and those into which it does not, or between regions into which the contrast agent distributes unequally.
For X-ray imaging, the contrast agents comprise relatively high atomic number atoms, e.g. barium or iodine, as X-ray transmission generally decreases as atomic number increases. For MR imaging however, the contrast agents are generally substances which affect the nuclear spin reequilibration of the nuclei (hereinafter the "imaging nuclei"--generally water protons in body tissues and fluids) which are responsible for the MR signals from which MR images are generated.
Accordingly, in recent years, many such substances have been suggested for use as MRI contrast agents. Thus, for example, in 1978 Lauterbur proposed the use of paramagnetic species, such as Mn(II), as MRI contrast agents (see Lauterbur et al., pages 752-759 in "Electrons to Tissues--Frontiers of Biologic Energetics", Volume 1, edited by Dutton et al., Academic Press, New York, 1978) and more recently Schering AG, in EP-A-71564, proposed the use of the dimeglumine salt of the gadolinium(III) chelate of diethylenetriaminepentaacetic acid (GdDTPA-dimeglumine).
Many other paramagnetic MRI contrast agents have been suggested in the literature and in this regard reference may be had to EP-A-71564 (Schering), EP-A-130934 (Schering), U.S. Pat. No. 4,615,879 (Runge), DE-A-3401052 (Schering), EP-A-185899 (Nycomed), EP-A-186947 (Nycomed), US. Pat. Nos. 2,387,735 (Bersworth), 2,407,645 (Bersworth), EP-A-165728 (Nycomed), U.S. Pat. Nos. 4,647,447 (Schering), 4,826,673 (Mallinckrodt), 4,639,365 (Sherry), EP-A-299795 (Nycomed), DE-A-2918842 (Rexolin Chemicals AB), EP-A-258616 (Salutar), DE-A-3633245 (Schering), EP-A-263059 (Schering), EP-A-277088 (Schering) and DE-A-3633243 (IDF) and in the documents cited in these patent publications.
Particularly interesting MRI contrast agents thus include chelates of paramagnetic metal species, e.g. Gd(III), Mn(II), Cr(III), Dy(III) and Fe(III) with cyclic or acyclic polyaminocarboxylic acids such as DOTA, DTPA, DTPA-bismethylamide, DTPA-bismorpholide, D03A, HP-D03A and derivatives thereof.
While MRI has until now mainly been used for imaging the central nervous system, the technique has great potential for imaging externally voided body cavities and especially the GI tract. However, development of MRI as a technique for imaging the GI tract, or indeed the abdomen in general, has been hindered by the special problems of imaging the abdomen in which, in the absence of a contrast agent, inter-tissue contrast is relatively poor and there is thus a general need for improved MRI contrast media suitable for imaging such body cavities.
Various substances have been evaluated as potential MRI contrast agents for the GI system, including for example paramagnetic compounds such as GdDTPA and GdDTPA-containing products are now in clinical trials as oral MRI contrast media (see for example Laniado et al. Fortschr. Rontgenstr. 147: 325-332 (1987), Kornmesser et al. Fortschr. Rontgenstr. 147: 550-556 (1987), Claussen et al. Fortschr. R',uml/o/ ntgenstr. 148: 683-689 (1988), Laniado et al., Chapter 23 in "Enhanced Magnetic Resonance Imaging", edited by Runge, St Louis, 1989, and EP-124766 (Schering AG).
Paramagnetic substances have a relatively close range effect on the imaging nuclei and thus, to be effective as positive contrast agents, need to be in close proximity (at the molecular level) to water molecules. During passage through the GI system however water is absorbed and as result the contrast efficiency of paramagnetic MRI contrast media administered into the GI tract is reduced.
This problem has been addressed by Schering by the inclus
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Hollinden Gary E.
Nycomed Imaging AS
Robinson Allen J.
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