Organic compounds -- part of the class 532-570 series – Organic compounds – Radioactive metal containing
Patent
1994-06-27
1996-12-17
Hollinden, Gary E.
Organic compounds -- part of the class 532-570 series
Organic compounds
Radioactive metal containing
534 14, 534 10, 530300, 5303915, 530408, 564 18, 564 23, 564 26, 564 28, 556 45, 556 64, 556 85, 556110, 556118, 560 18, 562432, 536 266, 552502, 552504, C07C33706, C07C33522, C07D20744, C07D21371
Patent
active
055854680
DESCRIPTION:
BRIEF SUMMARY
1. FIELD OF THE INVENTION
This invention relates to chelating agents useful for coupling metal ions to biologically active molecules.
2. BACKGROUND OF THE INVENTION
It has been discovered that antibodies and certain peptides can be used as highly specific vehicles for the delivery of drugs or radioisotopes to target organs, tumors or thrombi in vivo. Methods have been reported for the direct labeling of antibodies with radioisotopes (Huang et al., 1980, J. Nucl. Med. 21:783; Rhodes et al., in "Tumor Imaging", Burchiel and Rhodes, eds., Masson: New York, p. 111, 1982; and Sundrehagen, 1982, Eur. J. Nucl. Med. 7:549), taking advantage of partial reduction of protein disulfide linkages to generate free thiol groups capable of binding radiometals such as technetium. Because not all proteins or peptides contain readily reducible disulfides and partial reduction may alter the biological activity relative to the native molecule, it would be desirable to utilize a bifunctional radiometal chelator to form a covalent radiometal-chelator-peptide/protein conjugate capable of targeting radiometals in-vivo.
Of particular interest in nuclear medicine is the radiometal technetium-99m, which is a preferred isotope for scintigraphic imaging applications (Pinkerton et al., 1985, J. Chem. Educ. 62:965). Technetium is one of a class of metal ions that form strong coordinate bonds with sulfur-containing compounds, particularly thiols (e.g., metallothonein), but also thioureas (Koponec et al. 1977, Radiochem. Radioanal. Lett. 29:171). Koponec et al. describe the binding of technetium by thioureas to form complexes. This illustrates that thiocarbonyl functional groups bind technetium and thus may be useful as one part of a technetium binding bifunctional chelator.
The use of radiolabelled chelator conjugates may be preferable over the direct labeling systems for a number of reasons. First, the chelator may provide metal complexes of greater in vivo stability. A second advantage arises if a metabolically cleavable group is included in the linking portion of the bifunctional chelator to allow for rapid clearance and decreased accumulation of radiolabelled protein in non-targeted tissue. Lastly, direct labeling may require attachment of the radioisotope to functional groups of the protein which may lower or otherwise interfere with the in vivo targeting of the peptide or protein.
A number of bifunctional chelating agents have been reported in the scientific literature. Tolman et al. (U.S. Pat. No. 4,732,864) have described the use of the cysteine rich, metal binding protein metallothonein and metallothionein fragments conjugated to targeting molecules. However this method suffers from the fact that metallothonein is itself a large molecule and it may be difficult to purify and characterize such conjugates.
Schwartz et al. (1991, Bioconjugate Chem. 2:333) describe a series of bifunctional technetium chelators based on pyridyl hydrazines. This method of binding the radiometal is novel, however these chelators may not be useful for binding site specifically to antibodies or glycoproteins through the oxidized carbohydrate since the technetium binding hydrazide end may preferentially react with the aldehydes. Chemical solutions to this problem are not described.
Fritzberg et al. (EP 0188526; 1988, Proc. Natl. Acad. Sci. U.S.A. 85:4025) have described several examples of bifunctional dithiolate diamide technetium chelators. However, such methods for chelation of technetium are cumbersome since the compounds must be pre-chelated to technetium and then conjugated to antibodies. Also such compounds require a free thiol group for technetium chelation. Since free thiols are somewhat unstable to oxidation/dimerization and may reduce protein disulfide bonds if exposed to protein, the thiol functions in the chelator must be protected (masked) during final synthesis and then deprotected before technetium chelation.
Yokoyama et al. (U.S. Pat. No. 4,287,362; 1986, Int. J. Nucl. Med. Biol. 12:425; 1987, J. Nucl. Med. 28:1027) describe bifunctiona
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Belinka, Jr. Benjamin A.
Coughlin Daniel J.
Cytogen Corporation
Hartley Michael G.
Hollinden Gary E.
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