Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-08-07
1995-03-07
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549 68, C07D33336, C07D33502
Patent
active
053959469
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a method of preparing a metal-radionuclide-labelled protein or proteinaceous material which is destined for diagnostic or therapeutic applications. It also relates to novel compounds useful in this method.
Radionuclide-labelled compounds may be used for diagnostic examinations, for example, into deviations in shape and function of internal organs and into the presence and location of pathological processes in the body. For this purpose a composition in which the radioactive compound is present is administered to the patient, for example, in the form of an injectable liquid. By means of suitable detection apparatuses, for example, a gamma camera, images of the organ or the pathological process in which the radioactive compound has been incorporated can be obtained by recording the emitted radiation, that is, by scanning.
Radioactive labelled biological macromolecules, in particular proteins and proteinaceous materials, for example, blood-cells, immunoglobulins, glycopeptides, monoclonal antibodies, for example, antimyosin and monoclonals against tumor antigens, and other proteins suitable for localization purposes, such as single- or two-chain urokinase, tissue plasminogen activator, plasmin and other plasmin derivatives, e.g., miniplasmin, present interesting perspectives for diagnostic applications. Certain proteins have a very large target organ specificity and, after having been administered into the patient's body, can react very selectively with biological macromolecules present therein; a good example of this is the selective reaction of antibodies or antibody fragments with antigens present in the body.
Various metal-radionuclides, provided they are bonded to tumor-selective biological macromolecules, such as the glycopeptide bleomycin, can successfully be used for the control of tumors and thus form a powerful tool in radiotherapy. The macromolecules used thus serve as vehicles to transport the desired radiation dose, i.e., the metal-radionuclide, to the tumor to be exposed to the radiation.
The direct labelling of a protein or a proteinaceous material with a metal-radionuclide has two disadvantages. First, the biologically active site of the protein necessary for a good target organ specificity or selectivity, may easily be blocked by this reaction so that the normal behavior of the biological macromolecule is disturbed. In addition, the affinity between metal-radionuclide and macromolecule often is insufficient, as a result of which the formed bond is not sufficiently stable to remain intact under physiological conditions. The administered material then is no longer useful, neither as a diagnostic--the behavior of the protein in the body can no longer be traced--nor as a therapeutic--the radiation dose is no longer transported to the desired site but causes an undesired radiation burden elsewhere.
In order to mitigate these disadvantages, it is suggested in European patent application 237150 to first treat proteinaceous substances which contain disulfide bonds with a disulfide reducing agent, for example, dithiothreitol, and to then react the reduced proteinaceous substance which now contains free metcanto groups specifically with a radionuclide species, for example, with Tc-99m-tartrate or -glucoheptonate. The disadvantage of this method is the reductive treatment of the protein, in which the protein is "unfolded" by breaking the disulfide bonds to the desired mercapto groups. Damage to the protein molecules may then easily occur.
In the past few years a great number of publications have appeared in which biological macromolecules, usually proteins or proteinaceous substances, have been described which are provided with chelating groups for a bond with the desired metal-radionuclide. Recent patent publications in this field are the U.S. Pat. Nos. 4,479,930, 4,511,550, 4,652,440 and 4,678,667, the European patent applications (EP) Nos. 83129, 173629 and 188256, the Netherlands patent application (NL) 8204108, and the PCT applications WO 85/03231 and WO 86/03010.
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Goedemans Wilhelmus T.
Panek Karel J.
Hey David A.
Raymond Richard L.
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