Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1998-12-30
2000-05-30
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 9364, 424 9363, 424 942, 424 935, 424 943, 514 58, 514836, 536 46, 536103, 536121, 534 16, A61B 5055, A61K 4940
Patent
active
060688319
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the subject that is characterized in the claims, i.e., new pseudopolyrotaxanes, agents that contain these compounds, the use of these compounds in diagnosis, and a process for the production of these compounds and agents.
Pseudopolyrotaxanes are compounds in which several ring-shaped molecules are strung on a suitable polymer backbone. Such high-molecular molecule structures are described by, i.a., A. Harada et al., J. Am. Chem. Soc. 1994, 116, 3192-96 and G. Wenz et al., Angew. Chem. [Applied Chemistry] 104, 201-204 (1992).
The contrast media that are currently used in clinical practice for the modern imaging processes nuclear spin tomography (MRI) and computer tomography (CT) [Magnevist.RTM., Pro Hance.RTM., Ultravist.RTM. and Omniscan.RTM.] are dispersed throughout the entire extracellular space of the body (intravascular space and interstice). This dispersion space comprises about 20% of the body volume.
Clinically, extracellular MRI contrast media were first used successfully in the diagnosis of cerebral and spinal disease processes since here a quite special situation arises with respect to the regional dispersion space. In the brain and the spinal cord, extracellular contrast media in the healthy tissue cannot leave the intravascular space owing to the blood-brain barrier. In the case of pathological processes with disruption of the blood-brain barrier (e.g., malignant tumors, inflammations, demyelinating diseases, etc.), regions develop inside the brain with increased blood-vessel-permeability to these extracellular contrast media (Schmiedl et al., MRI of Blood-Brain Barrier Permeability in Astrocytic Gliomas: Application of Small and Large Molecular Weight Contrast Media, Magn. Reson. Med. 22: 288, 1991). By exploiting this disruption of vascular permeability, diseased tissue can be detected compared to healthy tissue with high contrast.
Outside of the brain and the spinal cord, however, there is no such permeability barrier to the above-mentioned contrast media (Canty et al., First-Pass Entry of Nonionic Contrast Agent into the Myocardial Extravascular Space. Effects on Radiographic Estimate of Transit Time and Blood Volume. Circulation 84: 2071, 1991). Thus, the concentration of the contrast medium no longer depends on vascular permeability, but rather only on the size of the extracellular space in the corresponding tissue. Delimitation of the vessels compared to the surrounding interstitial space using this contrast medium is not possible.
Especially for visualizing vessels, a contrast medium that disperses only into vascular space would be desirable. Such, a blood-pool agent should make it possible, with the aid of nuclear spin tomography, to delimit tissue that is well supplied with blood from tissue that is poorly supplied with blood and thus to diagnose an ischemia. It is also possible to delimit infarcted tissue, owing to its anemia, from surrounding healthy or ischemic tissue when a vascular contrast medium is used. This is of special importance if, e.g., the point is to distinguish a cardiac infarction from an ischemia.
To date, most patients in whom cardiovascular disease is suspected (this disease is the number-one cause of death in the Western industrialized countries) have to undergo invasive diagnostic studies.
There is therefore a need for NMR and x-ray contrast media that can label the vascular space (blood-pool-agent). These compounds are to be distinguished by good compatibility and high effectiveness (large increase in signal intensity in MRI).
To date, the attempt to solve at least a portion of this problem by using complexes that are bonded to macromolecules or biomolecules has been successful to an only very limited extent.
Thus, for example, the number of paramagnetic centers in the complexes, which are described in European Patent Applications No. 0 088 695 and No. 0 150 844, is not sufficient to ensure satisfactory imaging.
If the number of metal ions required is increased by repeatedly introducing complexing units into a macromolecular biomolecul
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patent: 5336762 (1994-08-01), Ranney
patent: 5855900 (1999-01-01), Nobuhiko
Harada, A. et al. Nature 364(6437):516-518, (Aug. 1993).
Raymo, F.M. et al. Trends in Polymer Science 4(7): 208-211, (Jul. 1996).
Cardenas, D.J. et al. J. American Chemical Society 119:2656-2664, (1997).
Platzek Johannes
Schmitt-Willich Heribert
Hollinden Gary E.
Schering Aktiengesellschaft
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