Organic compounds -- part of the class 532-570 series – Organic compounds – Rare earth containing
Patent
1990-07-26
1993-05-04
Stoll, Robert L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Rare earth containing
424 11, 424 9, 534 15, 436173, 5303915, 536 171, 536 51, 536101, 536112, 536113, 536121, A61K 4900
Patent
active
052083241
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to macromolecular paramagnetic compounds, to contrast agents containing such compounds and their use in magnetic resonance imaging (MRI) of human and non-human subjects, to chelating agents for use in the manufacture of such compounds and to the use of such chelating agents and chelates and and salts thereof in therapy and diagnosis.
In MRI, the contrast in the images generated may be enhanced by introducing into the zone being imaged an agent which affects the spin reequilibration characteristics of the nuclei (the "imaging nuclei", which are generally protons and more especially water protons) which are responsible for the resonance signals from which the images are generated. In this respect it has been found that contrast enhancement results from the use of contrast agents containing paramagnetic, superparamagnetic or ferromagnetic species. For paramagnetic contrast agents, the enhanced image contrast derives predominantly from the reduction in the spin reequilibration coefficient known as T.sub.1 or as the spin-lattice relaxation time, a reduction which arises from the effect on the imaging nuclei of the fields generated by the paramagnetic centres.
The use of paramagnetic compounds as contrast agents in MRI has been widely advocated and a broad range of paramagnetic compounds has been suggested in this regard. 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. B 289: 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 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'-ethylenediaminetetraacetic 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 and DE-A-3401052), and Nycomed AS have suggested the use of paramagnetic metal chelates of iminodiacetic acids (see EP-A-165728). Many other paramagnetic contrast agents have been suggested in the literature, for example in EP-A-230893, EP-A-232751, EP-A-292689, EP-A-255471, EP-A-292689, EP-A-287465, U.S. Pat. No. 4,687,659 and WO86/02005. Besides the chelates of DOTA and DTPA, the chelates of N,N" (bis methyl-carbamoylmethyl) N,N',N"-diethylenetriamine triacetic acid (DTPA-BMA), 1-oxa-4,710-triazacyclododecane-N,N',N"-triacetic acid (OTTA) and N-[2,3-dihydroxy-N-methyl-propylcarbamoylmethyl]-1,4,7,10-tetraazacyclodod ecane-N',N",N'"-triacetic acid, etc. (DO3A) deserve particular mention.
Paramagnetic compounds in which the paramagnetic centre is bound in a chelate complex have been considered particularly desirable as otherwise toxic heavy metals, such as gadolinium for example, may in this way be presented in a biotolerable form. The use of chelating agents, such as EDTA, DTPA, etc., known for their efficacy as heavy metal detoxification agents has thus received particular attention (see for example Weinmann et al., In AJR 142: 619-624 (1984)).
While the toxicities of the paramagnetic chelates are generally lower than those of the inorganic salts of the same paramagnetic metal species, the efficiency of such chelate complexes in contrast enhancement is not greatly improved relative to that of the salts.
It has however been found that by binding the paramagnetic species to a relatively heavy carrier, for example a macromolecule, increased contrast effect can be achieved, perhaps at least in part due to the effect of the heavy carrier in slowing down tumbling motions of the paramagnetic species. This is well illustrated by Technicare Corporation in EP-A-1368
REFERENCES:
patent: 4124705 (1978-11-01), Rothman et al.
patent: 4615879 (1986-10-01), Runge et al.
patent: 4639365 (1987-01-01), Sherry
patent: 4687659 (1987-08-01), Quay
patent: 4699784 (1987-10-01), Shih et al.
patent: 4714607 (1987-12-01), Klaveness
patent: 4741900 (1988-05-01), Alvarez et al.
patent: 4985233 (1991-01-01), Klaveness et al.
patent: 4986980 (1991-01-01), Jacobsen
patent: 5047227 (1991-09-01), Rodwell et al.
patent: 5057313 (1991-10-01), Shih et al.
Runge et al., "Paramagnetic Agents for Contrast-Enhanced NMR Imaging: A Review", 1983, pp. 1209-1215.
Mendonca-Dias et al., "Paramagnetic Contrast Agents in Nuclear Magnetic Resonance Medical Imaging", Seminars in Nuclear Medicine, vol. XIII, No. 4, Oct., 1984, pp. 364-376.
Brasch, "Work in Progress: Method of Contrast Enhancement for NMR Imaging and Potential Applications", 1983, pp. 781-788.
Koutcher, et al, "Adjunctive Medical Knowledge", The Journal of Nuclear Medicine, vol. 25, No. 4, 1984, pp. 506-513.
Schmiedl et al., "Albumin Labeled with Gd-DTPA as an Intravascular, Blood Pool--Enhancing Agent for MR Imaging: Biodistribution and Imaging Studies", 1987, pp. 205-210.
Weinmann et al., "Characteristics of Gadolinium-DTPA Complex: A Potential NMR Contrast Agent", 1984, pp. 619-624.
Runge et al., "Work in Progress: Potential Oral and Intravenous Paramagnetic NMR Contrast Agents", 1983, pp. 789-791.
Doyle et al., "Nuclear Magnetic Resonance (NMR) Imaging Symposium", Journal of Computer Assessed Tomography, vol. 5, No. 2, 1981, pp. 295-296.
Lauterbur, "Progress in n.m.r. zeugmatographic imaging", Phil. Trans. R. Soc. Lond. B 289, 1980, pp. 483-487.
Lauterbur, et al., "Augmentation of Tissue Water Proton Spin-Lattice Relaxation Rates by in vito Addition of Paramagnetic Ions", 1978, pp. 752-759.
Klaveness Jo
Rongved Pal
Strande Per
Nycomed Imaging AS
Sayala C.
Stoll Robert L.
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