Bisaminoethanethiol-targeting ligand conjugates and compositions

• US 8,236,279 B2
• Filed: 09/21/2009
• Issued: 08/07/2012
• Est. Priority Date: 10/25/1999
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Yang, David J., Liu, Chun W., Yu, Dong-Fang, Kim, E. Edmund
• Primary Examiner(s): Jones, D L
• Application Number:
  US12/563,724
• Publication Number:
  US 20100055035A1
• Time in Patent Office: 1,051 Days
• Field of Search: 424/1.11, 424/1.49, 424/1.53, 424/1.65, 424/1.69, 424/1.73, 424/9.1, 534/7, 534 10- 16, 530/300
• US Class Current: 424/1.65
• CPC Class Codes: A61K 51/0453 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 51/0459 having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61K 51/087 the peptide being an annexin, e.g. annexin V
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention provides, in a general sense, a new labeling strategy employing ^99mTc chelated with ethylenedicysteine (EC). EC is conjugated with a variety of ligands and chelated to ^99mTc for use as an imaging agent for tissue-specific diseases. The drug conjugates of the invention may also be used as a prognostic tool or as a tool to deliver therapeutics to specific sites within a mammalian body. Kits for use in tissue-specific disease imaging are also provided.

Claims

1. A bis-aminoethanethiol (BAT)-targeting ligand conjugate, wherein the targeting ligand is an agent that mimics glucose;

a folate receptor targeting ligand;

or a tumor hypoxia targeting ligand that is annexin V, colchicine, nitroimidazole, mitomycin, or metronidazole.

2. The conjugate of claim 1, wherein the conjugate is further defined as an ethylenedicysteine-targeting ligand conjugate.

3. The conjugate of claim 1, wherein the targeting ligand is an agent that mimics glucose.

4. The conjugate of claim 3, wherein the agent that mimics glucose is glucosamine, deoxyglucose, neomycin, kanamycin, gentamicin, paromycin, amikacin, tobramycin, netilmicin, ribostamycin, sisomicin, micromicin, lividomycin, dibekacin, isepamicin, astromicin, or an aminoglycoside.

5. The conjugate of claim 4, wherein the agent that mimics glucose is glucosamine.

6. The conjugate of claim 5, wherein the conjugate is further defined as EC-glucosamine.

7. The conjugate of claim 4, wherein the agent that mimics glucose is deoxyglucose.

8. The conjugate of claim 7, wherein the conjugate is further defined as EC-deoxyglucose.

9. The conjugate of claim 1, wherein the targeting ligand is a folate receptor targeting ligand.

10. The conjugate of claim 1, wherein the targeting ligand is a tumor hypoxia targeting ligand that is annexin V, colchicine, nitroimidazole, mitomycin, or metronidazole.

11. The conjugate of claim 1, wherein the conjugate further comprises a linker between said BAT and said targeting ligand.

12. The conjugate of claim 11, wherein the linker is a water soluble peptide, glutamic acid, polyglutamic acid, aspartic acid, polyaspartic acid, bromoethylacetate, ethylenediamine or lysine.

13. The conjugate of claim 1, wherein the bis-aminoethanethiol (BAT)-targeting ligand conjugate is labeled with a metal ion.

14. The conjugate of claim 13, wherein the metal ion is a radionuclide.

15. The conjugate of claim 14, wherein the radionuclide is ^99mTc, ¹⁸⁸Re, ¹⁸⁶Re, ¹⁸³Sm, ¹⁶⁶Ho, ⁹⁰Y, ⁸⁹Sr, ⁶⁷Ga, ⁶⁸Ga, ¹¹¹In, ¹⁵³Gd, ⁵⁹Fe, ²⁵⁵Ac, ²¹²Bi, ²¹¹At, ⁶²Cu, or ⁶⁴Cu.

16. The conjugate of claim 1, wherein the BAT comprises two carboxylic acid moieties.

17. The conjugate of claim 16, wherein a targeting ligand is conjugated to one of the carboxylic acid moieties of the BAT.

18. The conjugate of claim 16, wherein a first targeting ligand is conjugated to one of the carboxylic acid moieties of the BAT and a second targeting ligand is conjugated to another carboxylic acid moiety of the BAT.