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Details for Patent: 5,997,844

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Details for Patent: 5,997,844

Title: Technetium-99m labeled peptides for imaging
Abstract:This invention relates to radiolabeled peptides and methods for producing such peptides. Specifically, the invention relates to peptides, methods and kits for making such peptides, and methods for using such peptides to image sites in a mammalian body labeled with technetium-99m (Tc-99m) via a radiolabel-binding moiety covalently attached to a specific binding peptide via an amino acid side-chain of the peptide.
Inventor(s): Dean; Richard T. (Bedford, NH), Buttram; Scott (Derry, NH), McBride; William (Manchester, NH), Lister-James; John (Bedford, NH), Civitello; Edgar R. (Bradford, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:Jun 03, 1994
Application Number:08/253,678
Claims:1. A composition comprising:

a) a peptide having specific binding properties and comprising from 3 to 100 amino acid residues, wherein one of said residues has a thiol sidechain; and

b) a radiolabel complexing moiety,

wherein:

the moiety is covalently linked to said sidechain, and

the specific binding properties of the peptide are retained.

2. The composition of claim 1 wherein the peptide and the moiety are covalently linked through a homocysteine residue.

3. A scintigraphic imaging agent comprising the composition of claim 1 and a radiolabel.

4. The agent of claim 3 wherein the radiolabel is technetium-99m, indium-111, or gallium-68.

5. A composition comprising:

a) a peptide having specific binding properties and comprising from 3 to 100 amino acid residues, wherein said residue has a sidechain comprising amine or thiol; and

b) a radiolabel complexing moiety having a formula selected from the group consisting of:

wherein Cp is a protected cysteine and (aa) is any primary .alpha.- or .beta.-amino acid not containing a thiol group; ##STR5## wherein X=H or a protecting group;

(amino acid)=any primary .alpha.- or .beta.-amino acid not containing a thiol group; ##STR6## wherein X=H or a protecting group;

(amino acid)=any primary .alpha.- or .beta.-amino acid not containing a thiol group; ##STR7## wherein each R.sup.5 is independently H, CH.sub.3 or C.sub.2 H.sub.5 ;

each (pgp).sup.S is independently a thiol protecting group or H;

m, n and p are independently 2 or 3;

A=linear lower alkyl, cyclic lower alkyl, aryl, heterocyclyl, or a combination thereof;

X=peptide;

and ##STR8## wherein each R.sup.5 is independently H, lower alkyl having 1 to 6 carbon atoms, phenyl, or phenyl substituted with lower alkyl or lower alkoxy;

m, n and p are independently 1 or 2;

A=linear lower alkyl, cyclic lower alkyl, aryl, heterocyclyl, or a combination thereof;

V=H or --CO-peptide;

R.sup.6 =H or peptide;

wherein when V=H, R.sup.6 =peptide and when R.sup.6 =H, V=--CO-peptide,

wherein:

the moiety is covalently linked to said sidechain; and

the specific binding properties of the peptide are retained.

6. The composition of claim 5 wherein the protected cysteine of formula I has a protecting group of a formula

wherein R is a lower alkyl group having 1 to 6 carbon atoms, 2-,3-,4-pyridyl, phenyl, or phenyl substituted with lower alkyl, hydroxy, lower alkoxy, carboxy, or lower alkoxycarbonyl.

7. The composition of claim 5, wherein the moiety has a formula: ##STR9##

8. A scintigraphic imaging agent comprising the composition of claim 5 and a radiolabel.

9. The agent of claim 8 wherein the radiolabel is technetium-99m, indium-111, or gallium-68.

10. A composition comprising: a) a peptide having specific binding properties and comprising from 3 to 100 amino acids; and

b) a radiolabel complexing moiety comprising a single thiol having a formula:

wherein

A is H, HOOC, H.sub.2 NOC, (amino acid or peptide)-NHOC, (amino acid or peptide)-OOC, or R.sup.4 ;

B is H, SH, --NHR.sup.3, --N(R.sup.3)-(amino acid or peptide), or R.sup.4 ;

X is H, SH, --NHR.sup.3, --N(R.sup.3)-(amino acid or peptide), or R.sup.4 ;

Z is a lower straight or branched chain or cyclic alkyl;

R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently H or lower straight or branched chain or cyclic alkyl;

n is 0, 1, or 2;

(peptide) is a peptide of 2 to about 10 amino acids; and

where B is --NHR.sup.3 or --N(R.sup.3)-amino acid or peptide), X is SH, and n is 1 or 2;

where X is --NHR.sup.3 or --N(R.sup.3)-amino acid or peptide), B is SH, and n is 1 or 2;

where B is H or R.sup.4, A is HOOC, H.sub.2 NOC, (amino acid or peptide)-NHOC, (amino acid or peptide)-OOC, X is SH, and n is 0 or 1;

where A is H or R.sup.4, then where B is SH, X is --NHR.sup.3 or --N(R.sup.3)-amino acid or peptide) and where X is SH, B is --NHR.sup.3 or --N(R.sup.3)-(amino acid or peptide);

where X is H or R.sup.4, A is HOOC, H.sub.2 NOC, (amino acid or peptide)-NHOC, (amino acid or peptide)-OOC, and B is SH;

where Z is methyl, X is methyl, A is HOOC, H.sub.2 NOC, (amino acid or peptide)-NHOC, (amino acid or peptide)-OOC, B is SH and n is 0;

and wherein the thiol is in the reduced form and (amino acid) is any primary .alpha.- or .beta.-amino acid not containing a thiol group:

wherein:

the moiety is covalently linked to a sidechain of an amino acid of the peptide; and

the specific binding properties of the peptide are retained.

11. The composition of claim 10, wherein the moiety is selected from the group consisting of:

and

wherein

(amino acid).sup.1 and (amino acid).sup.2 are each independently any naturally-occurring, modified, substituted, or altered .alpha.- or .beta.-amino acid not containing a thiol group.

12. A scintigraphic imaging agent comprising the composition of claim 10 and a radiolabel.

13. The agent of claim 12 wherein the radiolabel is technetium-99m, indium-111, or gallium-68.

14. A composition comprising:

a) a peptide selected from the group consisting of:

formyl-MLF

(VGVAPG).sub.3 amide

(VPGVG).sub.4 amide

RALVDTLKFVTQAEGAKamide (SEQ ID NO.:1);

RALVDTEFKVKQEAGAKamide (SEQ ID NO.:2);

PLARITLPDFRLPEIAIPamide (SEQ ID NO.:3);

GQQHHLGGAKAGDV (SEQ ID NO.:4);

PLYKKIIKKLLES (SEQ ID NO.:5);

LRALVDTLKamide (SEQ ID NO.:6);

GGGLRALVDTLKamide (SEQ ID NO.:7);

GGGLRALVDTLKFVTQAEGAKamide (SEQ ID NO.:8);

GGGRALVDTLKALVDTLamide (SEQ ID NO.:9);

GHRPLDKKREEAPSLRPAPPPISGGGYR (SEQ ID NO.:10);

PSPSPIHPAHHKRDRRQamide (SEQ ID NO.:11);

GGGF.sub.D.Cpa.YW.sub.D KTFTamide; ##STR10## (SYNRGDSTC).sub.3 -TSEA GGGLRALVDTLKamide (SEQ ID NO.:13);

GCGGGLRALVDTLKamide (SEQ ID NO.:14);

GCYRALVDTLKFVTQAEGAKamide (SEQ ID NO.:15); and

GC(VGVAPG).sub.3 amide; and

b) a radiolabel complexing moiety;

wherein:

the moiety is covalently linked to a sidechain of an amino acid of the peptide; and

the specific binding properties of the peptide are retained.

15. A composition comprising:

a) a multiplicity of peptides having specific binding properties;

b) a radiolabel complexing moiety covalently linked to a sidechain of an amino acid of each peptide; and

c) a polyvalent linking moiety covalently linked to each peptide,

thereby forming a multimeric polyvalent reagent having a molecular weight less than about 20,000 daltons.

16. The composition of claim 15 wherein the polyvalent linking moiety is selected from the group consisting of bis-succinimidylmethylether, 4-(2,2-dimethylacetyl)benzoic acid, N-(2-(N',N'-bis(2-succinimido-ethyl)aminoethyl))-N.sup.6,N.sup.9 -bis(2-methyl-2-mercaptopropyl)-6,9-diazanonanamide, tris(succinimidylethyl)amine, tris(acetamidoethyl)amine, bis(acetamidoethyl)ether, bis-(acetamidomethyl)ether, .alpha.,.epsilon.-bisacetyllysine, lysine and 1,8-bis-acetamido-3,6-dioxa-octane.

17. A complex formed by reacting the composition of claim 1 with technetium-99m in the presence of a reducing agent.

18. The complex of claim 17, wherein the reducing agent is selected from the group of a dithionite ion, a stannous ion, or a ferrous ion.

19. A complex formed by labeling the composition of claim 1 with technetium-99m by ligand exchange of a prereduced technetium-99m complex.

20. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the composition of claim 1 and a sufficient amount of a reducing agent to label the reagent with technetium-99m.

21. A method of imaging a site within a mammalian body comprising the steps of administering an effective diagnostic amount of the agent of claim 4 and detecting the radiolabel localized at said site.

22. A process of preparing the composition of claim 1, wherein the peptide is chemically synthesized in vitro.

23. The process of claim 22, wherein the peptide is synthesized by solid phase peptide synthesis.

24. The composition of claim 1 wherein the peptide and the moiety comprise a cyclic peptide.

25. The composition of claim 5 wherein the moiety has formula: ##STR11## wherein X=H or a protecting group; and

(amino acid)=any primary .alpha.- or .beta.-amino acid not containing a thiol group.

26. The composition of claim 5 wherein the moiety has formula: ##STR12## wherein X=H or a protecting group; and

(amino acid)=any primary .alpha.- or .beta.- amino acid not containing a thiol group.

27. The composition of claim 5 wherein the moiety has formula: ##STR13## wherein each R.sup.5 is independently H, CH.sub.3 or C.sub.2 H.sub.5 ;

each (pgp).sup.S is independently a thiol protecting group or H;

m, n and p are independently 2 or 3;

A=linear lower alkyl, cyclic lower alkyl, aryl, heterocyclyl, or a combination thereof;

X=peptide.

28. The composition of claim 5 wherein the moiety has formula: ##STR14## wherein each R.sup.5 is independently H, lower alkyl having 1 to 6 carbon atoms, phenyl, or phenyl substituted with lower alkyl or lower alkoxy;

m, n and p are independently 1 or 2;

A=linear lower alkyl, cyclic lower alkyl, aryl, heterocyclyl, or a combination thereof;

V=H or --CO-peptide;

R.sup.6 =H or peptide;

and wherein when V=H, R.sup.6 =peptide and when R.sup.6 =H, V=--CO-peptide.

29. The composition of claim 14 wherein the peptide has the amino acid sequence PLYKKIKKLLES.
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