Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1987-06-30
1993-10-05
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 172, 536 174, 536 53, 536121, 536101, 536102, 536103, 536112, 436173, 1286532, 424 9, C07H 1702, C07H 2300, G01N 2400, A61B 505
Patent
active
052506720
DESCRIPTION:
BRIEF SUMMARY
Nitroxyl spin label (NSL) compounds are stable free radicals having the general formula: ##STR1## where X is a chain of two or three carbon atoms which may be substituted. NSL compounds have potential as paramagnetic agents for nuclear magnetic resonance (NMR) imaging because of a chemically stable unpaired electron. When NSL compounds are placed in a magnetic field, the electron aligns with the field; as a much stronger magnetic dipole than unpaired protons, the unpaired electron alters the local magnetic field experienced by protons around it, reducing T.sub.1 and T.sub.2 relaxation times.
Many different NSL compounds are available commercially; others can readily be synthesized using methods described in the literature. The potential of NSL compounds as contrast agents for NMR imaging is qualified by the fact that they are somewhat unstable in vivo. NSL compounds have been reported for the NMR imaging of kidneys (V. M. Runge (1983) Radiology 147 789) and tumors (R. L. Ehman (1985) 3 Magnetic Resonance Imaging). NSL compounds have been studied in vitro (J. D. Lovin (1985) Magnetic Resonance Imaging 3 73) and have been shown to be unstable to high concentrations of ascorbic acid being readily reduced to hydroxylamine (W. R. Couet (1984) Pharm. Res. 5 203).
NSL compounds have been used to label various compounds of biological interest. In particular two authors have reported the spin-labelling of polysaccharides. M. J. Adam et al (Carbohydrate Research (1979) 68, C17 to C20) used a triazine reagent but achieved only a limited degree of conjugation. T. P. Mawhinney et al (Carbohydrate Research (1983) 116, C1 to C4) used a carbanion reagent and achieved greater conjugation. But neither author suggests that the complexes might be useful as contrast agents for NMR imaging in vivo.
In one aspect, the present invention comprises the use of a polysaccharide-NSL complex for the preparation of an NMR diagnostic composition. In another aspect, it comprises the use of a polysaccharide-NSL complex as a contrast agent for NMR imaging.
The nature of the NSL compound is not critical to the invention. The NSL compound may be as described above. Our work has been primarily concerned with the compound-4 amino-2,2,6,6,-tetramethylpiperidine-1-oxyl (4-aminoTEMPO).
Various different polysaccharides, including chemical derivatives thereof, may be used, and will have an important influence on the properties of the complex. The polysaccharide may be water-soluble, such as dextran or dextrin, or water-insoluble, such as cellulose or sepharose or starch. Sepharose is a bead-formed gel prepared by cross-linking agarose. Other possible starches include amylose, xylan, mannan, locust-bean gum and guar gum. Compositions based on water-soluble polysaccharides may be administered orally or parenterally; compositions based on water-insoluble polysaccharides are mainly suitable for oral administration.
The polysaccharide may be metabolizable or non-metabolizable by the animal to which it is administered, or by its intestinal flora. Compounds which are not metabolized within the time span required for NMR scanning are regarded herein as non-metabolizable, even though they may be metabolized over a much longer time span. Cellulose, sepharose and dextran are non-metabolizable by humans, whereas starch and dextrin are metabolizable.
The polysaccharide-NSL complexes may be prepared by methods well described in the literature. The polysaccharide may first be activated, e.g. by means of chloroacetic acid or cyanogen bromide, followed by reaction with the NSL compound. Suitable reaction conditions are indicated in the examples below. In some of our studies chloroacetic acid has often proved a more effective activating agent than cyanogen bromide.
In another aspect, this invention provides an agent for modifying relaxation times in NMR diagnosis comprising a polysaccharide to which is chemically linked both an NSL compound and an organic complexant to which is complexed a paramagnetic metal ion.
Agents for modifying relaxation times in NMR diagnosi
REFERENCES:
patent: 3966744 (1976-06-01), Goldstein et al.
patent: 3966764 (1976-06-01), Goldstein et al.
Keana, Newer Aspects of the Synthesis and Chemistry of Nitroxide Spin Labels, "Chemical Reviews", 78(1) 37-64 (1978).
Ehman et al., Diradical Nitroxyl Spin Label Contrast Agents for Magnetic Reasonance Imaging, A Comparison of Relaxation Effectiveness; "Investigative Radiology", 21 125-131 (Feb. 1986).
Brasch et al., (Jun. 1983) "Work in Progress: Nuclear Magnetic Resonance Study of a Paramagnetic Nitroxide Contrast Agent for Enhancement of Renal Structures in Experimental Animals, Radiology", 147: pp. 773-779.
Harding Charles T.
Sadler Peter J.
Brown Johnnie R.
Guerbet S.A.
White Everett
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