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Details for Patent: 5,552,525

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Details for Patent: 5,552,525

Title: Technetium-99m labeled peptides for imaging inflammation
Abstract:This invention relates to reagents, radiolabeled reagents and methods for producing such reagents and radiolabeled reagents. Specifically, the invention relates to technetium-99m (Tc-99m) labeled peptides that specifically bind to inflammatory sites in vivo, methods and kits for making such peptides, and methods for using such peptides to image sites of infection and inflammation in a mammalian body.
Inventor(s): Dean; Richard T. (Bedford, NH)
Assignee: Diatech Inc. (Londonderry, NH)
Filing Date:Feb 19, 1993
Application Number:08/019,864
Claims:1. A reagent for preparing a technetium-99m (Tc-99m) radiolabeled peptide for imaging sites of inflammation within a mammalian body, comprising a specific binding peptide comprising platelet factor 4 or peptide fragments thereof wherein the peptide specifically binds to sites of inflammation, covalently linked to a Tc-99m binding moiety.

2. A reagent for preparing a technetium-99m (Tc-99m) radiolabeled peptide for imaging sites of inflammation within a mammalian body, comprising a specific binding peptide comprising platelet factor 4 or peptide fragments thereof wherein the peptide specifically binds to sites of inflammation, covalently linked to a Tc-99m binding moiety of formula selected from the group consisting of:

wherein Cp is a protected cysteine and (aa) is an amino acid;

wherein

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

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

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

Z is H or R.sup.4 ;

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;

and

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

where X is --NHR.sup.3 or --N(R.sup.3)-(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, (peptide)-NHOC, (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)-(peptide) and where X is SH, B is --NHR.sup.3 or --N(R.sup.3)-(peptide);

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

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

where B is SH and X is SH, n is not 0;

and wherein the thiol moiety is in the reduced form; and ##STR5## wherein X.dbd.H or a protecting group;

(amino acid)=any amino acid; ##STR6## wherein each R.sup.5 is independently H, CH.sub.3 or C.sub.2 H.sub.5 ;

each (pgp).sup.5 is independently a thiol protecting group or H;

m, n and p are independently 2 or 3;

A=linear or cyclic lower alkyl, aryl, heterocyclyl, combinations or substituted derivatives thereof; ##STR7## 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 or cyclic lower alkyl, aryl, heterocyclyl, combinations or substituted derivatives 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;

wherein the radiolabel-binding moiety forms a complex with a radioisotope and the complex is electrically neutral.

3. The reagent of claim 2 wherein the specific binding peptide and Tc-99m binding moiety are covalently linked through one or more amino acids.

4. The reagent of claim 2 wherein the protected cysteine of the Tc-99m binding moiety having formula I has a protecting group of the formula

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

5. The reagent of claim 2 wherein the Tc-99m binding moiety of formula Cp(aa)Cp has the formula: ##STR8##

6. The reagent according to claim 2 wherein the Tc-99m binding moiety is bound to Tc-99m.

7. The reagent of claim 2 wherein the specific binding peptide is selected from the group consisting of peptides having the amino acid sequence PLYKKIIKKLLES (SEQ ID NO.:7) and KKIIKKLLES (SEQ ID No.:8).

8. The reagent of claim 1 wherein the reagent further comprises a polyvalent linking moiety covalently linked to a multiplicity of specific binding peptides and also covalently linked to a multiplicity of radiolabel-binding moieties to comprise a multimeric polyvalent scintigraphic imaging agent, wherein the molecular weight of the multimeric polyvalent scintigraphic imaging agent is less than about 20,000 daltons.

9. The reagent of claim 8 that is a multimeric polyvalent scintigraphic imaging agent, wherein the polyvalent linking moiety is bis-succinimidylmethylether, 4-(2,2-dimethylacetyl)benzoic acid, diethylenetriaminepentaacetic acid, tris(succinimidylethyl)amine or a derivative thereof.

10. A complex formed by reacting the reagent of claim 2 with technetium-99m in the presence of a reducing agent.

11. The complex of claim 10, wherein the reducing agent is selected from the group of a dithionite ion, a stannous ion, or a ferrous ion.

12. A complex formed by labeling the reagent of claim 2 with technetium-99m by ligand exchange of a prereduced technetium-99m complex.

13. A kit for preparing a radiopharmaceutical preparation, said kit comprising sealed vial containing a predetermined quantity of the reagent of claim 2 and a sufficient amount of reducing agent to label the reagent with technetium-99m.

14. The process of preparing the reagent according to claim 2 wherein the reagent is chemically synthesized in vitro.

15. The process of preparing the reagent according to claim 14 wherein the specific binding peptide is synthesized by solid phase peptide synthesis.

16. The reagent according to claim 2 wherein the radiolabel binding moiety is covalently linked to the specific binding peptide during in vitro chemical synthesis.

17. The reagent according to claim 16 wherein the radiolabel binding moiety is covalently linked to the specific binding peptide during solid phase peptide synthesis.

18. A method for labeling a peptide according to claim 2 comprising reacting the peptide with Tc-99m in the presence of a reducing agent.

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

20. A composition of matter comprising the reagent of claim 2 having the formula:

21. A composition of matter having the formula: ##STR9##

22. A composition of matter comprising the reagent of claim 2 having the formula:

23. A composition of matter comprising the reagent of claim 2 having the formula:

24. A composition of matter comprising the reagent of claim 2 having the formula:

25. A composition of matter comprising the reagent of claim 2 having the formula:

26. A composition of matter comprising the reagent of claim 2 having the formula:

27.

27. A composition of matter having the formula: ##STR10##
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