Radionuclide metal N.sub.2 S.sub.2 chelates substituted with glu

Details Radionuclide metal N.sub.2 S.sub.2 chelates substituted with glu Radionuclide metal N.sub.2 S.sub.2 chelates substituted with glu

1996-03-11

1998-07-21

Hollinden, Gary E.

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

424 165, 424 169, 534 10, 534 13, 534 14, 5483037, 5483041, A61K 5100, C07F 500, C07D23502

Patent

active

057831718

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND

Radiolabeled antibodies are used in a variety of diagnostic and therapeutic medical procedures. The increased specificity of monoclonal antibodies, compared to polyclonal antibodies, makes them even more useful for delivering diagnostic or therapeutic agents such as radioisotopes to desired target sites in vivo. A monoclonal antibody specific for a desired type of target cells such as tumor cells may be used to deliver a therapeutic radionuclide attached to the antibody to the target cells, thereby causing the eradication of the undesired target cells. Alternatively, a monoclonal antibody having a diagnostically effective radionuclide attached thereto may be administered, whereupon the radiolabeled antibody localizes on the target tissue. Conventional diagnostic procedures then may be used to detect the presence of the target sites within the patient. In contrast to such "chelate-labeled antibody" procedures, pretargeting approaches may be used to achieve therapeutic or diagnostic goals, which pretargeting approaches involve the interaction of two members of a high affinity binding pair such as a ligand-anti-ligand binding pair.
One method for radiolabeling proteins such as antibodies as well as proteinaceous and non-proteinaceous binding pair members involves attachment of radionuclide metal chelates to the proteins or binding pair members. Chelates having a variety of chemical structures have been developed for this purpose. The usefulness of such chelates is dependent upon a number of factors such as the stability of radionuclide binding within the chelate and the reactivity of the a chelate with the desired protein or binding pair member. The efficiency of radiolabeling of the chelating compound to produce the desired radionuclide metal chelate also is important. Another consideration is the biodistribution of the radiolabeled antibody or binding pair member and catabolites thereof in vivo. Localization in non-target tissues limits the total dosage of a therapeutic radiolabeled antibody or binding pair member that can be administered, thereby decreasing the therapeutic effect. In diagnostic procedures, localization in non-target tissues may cause undesirable background and/or result in misdiagnosis. The need remains for improvement in these and other characteristics of radionuclide metal chelate compounds used for radiolabeling of proteins such as antibodies. The use of pretargeting approaches diminishes non-target tissue localization of radiolabel; however, the need remains for improvement in molecules incorporating chelates and binding pair members of proteinaceous or non-proteinaceous structure.


SUMMARY OF THE INVENTION

The present invention provides a compound of the formula: ##STR1## wherein: each R independently represents .dbd.O, H.sub.2, a lower alkyl group, --(CH.sub.2).sub.n -- COOH, --(CH.sub.2).sub.n --CO-saccharide or saccharide derivative, or --(CH.sub.2).sub.n --NH-saccharide or saccharide derivative, or R.sub.1 --Z; anti-ligand conjugation group or a targeting protein, ligand or anti-ligand; or a ligand-linker moiety or an anti-ligand-linker moiety wherein the linker moiety is derived from a ligand or anti-ligand conjugation group; --(CH.sub.2).sub.n -- COOH, --(CH.sub.2).sub.n --CO-saccharide or saccharide derivative, or --(CH.sub.2).sub.n --NH-saccharide or saccharide derivative, or R.sub.1 --Z; one --(CH.sub.2).sub.n --CO-saccharide or saccharide derivative or --(CH.sub.2).sub.n --NH-saccharide or saccharide derivative substituent and one --R.sub.1 --Z substituent.
The present invention also provides radionuclide metal chelate compounds of the formula: ##STR2## wherein: M represents a radionuclide metal or oxide thereof and the other symbols are as described above.
These compounds comprise a targeting protein such as an antibody, or a conjugation group for attachment of the compound to a targeting protein. Alternatively, the compounds include a ligand or an anti-ligand or a conjugation group for the attachment of the compound to a ligand or to an anti-ligand. The chela

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patent: 5541287 (1996-07-01), Yau et al.
patent: 5578287 (1996-11-01), Theodore et al.

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