Small technetium-99m and rhenium labeled agents and methods for imaging tumors

• US 20040097735A1
• Filed: 10/23/2002
• Published: 05/20/2004
• Est. Priority Date: 04/28/2000
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), Massachusetts Institute of Technology
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation), Massachusetts Institute of Technology
• Inventors: Friebe, Matthias, Bolzati, Cristina, Davison, Alan, Mahmood, Ashfaq, Jones, Alun G.
• Granted Patent: US 7,321,027 B2
• Time in Patent Office: Days
• US Class Current: 546/2
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 323/41 Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Abstract

The present invention relates to compounds and related technetium and rhenium complexes thereof which are suitable for imaging or therapeutic treatment of tumors, e.g., carcinomas, melanomas and other tumors. In another embodiment, the invention relates to methods of imaging tumors using radiolabeled metal complexes. Preferred radiolabeled complexes for imaging tumors include technetium and rhenium complexes. The high tumor uptake and significant tumor/nontumor ratios of the technetium complexes of the invention indicate that such small technetium-99m-based molecular probes can be developed as in-vivo diagnostic agents for melanoma and its metastases. In yet another embodiment, the invention relates to methods of treatment of tumors using a radiolabeled metal complex as a radiopharmaceutical agent to treat the tumor.

Claims

1. A compound capable of binding a metal ion, the compound according to the formula:

2. The compound of claim 1, wherein the compound is capable of binding a metal ion selected from the group consisting of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum and rhodium.

3. The compound of claim 1, wherein the compound is capable of binding technetium or rhenium.

4. The compound of claim 1, wherein NR₁R₂ taken in combination form a heterocyclic ring having 5, 6 or 7 ring atoms.

5. The compound of claim 4, wherein the heterocyclic ring is a heterocycle according to the formula:

6. The compound of claim 5, wherein —

NR₁R₂ taken in combination is N-morpholino or N-piperidinyl.

7. The compound of claim 1, according go the formula:

8. The compound of claim 1, according go the formula:

.

9. The compound of claim 1, according go the formula:

10. A neutral or cationic radiolabeled complex comprising a compound of claim 1 and a metal ion.

11. A neutral or cationic radiolabeled complex of claim 10, wherein the metal ion is selected from the group consisting of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum and rhodium.

12. A neutral or cationic radiolabeled complex of claim 10, wherein the metal ion is technetium-99m or one or more isotopes of rhenium.

13. A radiolabeled complex of claim 12, wherein the complex is of the formula:

14. A radiolabeled complex of claim 12, wherein the complex is of the formula:

15. A method for in-vivo or in-vitro imaging of at least one tumor comprising the steps of:

providing a radiolabeled complex comprising a metal ion and a compound of the following structure;

Y—

X—

NR₁R₂

wherein

Y is a chelating ligand capable of binding the metal ion;

X is a linking group comprising a backbone chain having 1 to about 8 atoms, the backbone chain can optionally include ester, amide, amine, ether or thioether linkages in the backbone chain and does not include aromatic groups integral to the backbone chain of the linking group; and

R₁ and R₂ each are independently selected from a lower alkyl group having 1 to about 4 carbon atoms, or

—

NR₁R₂ taken in combination is a heterocyclic ring having 3 to about 8 ring atoms and 1 or 2 hetero ring atoms;

contacting the tumor(s) with the radiolabeled metal complex; and

making a radiographic image to image the tumor(s).

16. A method of claim 15, wherein the metal ion is selected from the group consisting of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum and rhodium.

17. A method of claim 15, wherein the metal ion is technetium-99m or one or more isotopes of rhenium.

18. A method of claim 15, wherein the tumor(s) are neoplasm(s).

19. A method of claim 15, wherein the tumor(s) are carcinoma(s).

20. A method of claim 15, wherein the tumor(s) are melanoma(s).

21. A method of claim 15, wherein the radiolabeled complex comprises a compound of the structure:

Y—

X—

NR₁R₂

wherein Y is a tetradentate chelating ligand capable of binding a metal ion selected from the group consisting of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum and rhodium.

22. A method of claim 21, wherein Y is a tetradentate chelating ligand capable of binding technetium-99m or at least one isotope of rhenium.

23. A method of claim 22, wherein the tetradentate chelating ligand, Y, is an amido-amino-dithiolate or diamino-dithiolate and the nitrogen and sulfur atoms capable of binding technetium are linked by ethylene or propylene groups wherein each carbon of the ethylene or propylene linker groups are substituted with one or more substituents chosen from the group consisting of hydrogen, lower alkyl having 1 to about 4 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, oxo, and —

XNR₁R₂.

24. A method of claim 23, wherein NR₁R₂ taken in combination is a heterocyclic ring according to the formula:

25. A method of claim 23, wherein the compound of the formula Y—

X—

NR₁R₂ is a compound of the formula;

26. A method of claim 25, wherein the compound is of the formula:

27. A method of claim 25, wherein the compound is of the formula:

28. A method of claim 25, wherein the compound is of the formula:

29. A method of claim 25, wherein the radiolabeled complex is of the formula:

30. A method of claim 25, wherein the radiolabeled complex is of the formula:

31. A method for the for treatment of cancer comprising the steps of:

providing a cytotoxic metal complex comprising a metal ion and a compound of the following structure;

Y—

X Y is a chelating ligand capable of binding the metal ion;

X is a linking group comprising a backbone chain having 1 to about 8 atoms, the backbone chain can optionally include ester, amide, amine, ether or thioether linkages in the backbone chain and does not include aromatic groups integral to the backbone chain of the linking group; and

R₁ and R₂ each are independently selected from a lower alkyl group having 1 to about 4 carbon atoms, or

—

NR₁R₂ taken in combination is a heterocyclic ring having 3 to about 8 ring atoms and 1 or 2 hetero ring atoms; and

contacting the tumor(s) with the cytotoxic metal complex.

32. A method of claim 31, wherein the metal ion is a radioactive isotope of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum, or rhodium.

33. A method of claim 32, wherein the chelating ligand, Y—

X—

NR₁R₂, is a compound of the formula;

34. A method of claim 33, wherein the radiolabeled complex is of the formula: