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Details for Patent: 6,019,958

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Details for Patent: 6,019,958

Title: Technetium-99m labeled peptides for imaging inflammation
Abstract:This invention relates to compositions that are radiolabeled scintigraphic imaging agents, comprising a polybasic compound covalently linked to a radiolabel binding moiety and the composition further comprising a polysulfated glycan. The invention also provides methods for producing and using such compositions. Specifically, the invention relates to compositions comprised of technetium-99m (Tc-99m) labeled scintigraphic imaging agents comprising a polybasic compound having at least 5 chemical functionalities that are basic at physiological pH and a radiolabel-binding moiety, the composition further comprising a polysulfated glycan, the composition being capable of accumulating at inflammatory sites in vivo. Methods and kits for making such compositions, and methods for using such compositions to image sites of infection and inflammation in a mammalian body, are also provided.
Inventor(s): Dean; Richard T. (Bedford, NH), Moyer; Brian R. (Bedford, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:Oct 04, 1996
Application Number:08/564,315
Claims:1. A composition comprising:

a) a reagent comprising:

i) a polybasic compound having a molecular weight from about 500 daltons to about 15,000 daltons and having at least 5 chemical functionalities that are basic at physiological pH; and

ii) a technetium-99m binding moiety covalently linked to the compound; and

b) a polysulfated glycan having a molecular weight of at least about 1,000 daltons;

wherein the composition is capable of accumulating at sites of inflammation in vivo.

2. The composition of claim 1, wherein the chemical functionalities are amines.

3. The composition of claim 1, wherein the polybasic compound is a peptide of 5 to 100 amino acids.

4. The composition of claim 3, wherein the peptide is platelet factor 4 or a fragment thereof.

5. The composition of claim 4, wherein the peptide comprises an amino acid sequence PLYKKIIKKLLES (SEQ ID NO:13) or KKIIKKILES (SEQ ID NO:14).

6. The composition of claim 5, wherein the peptide has an amino acid selected from the group consisting of

acetyl-KKKKKCGCGGPLYKKIIKKLLES (SEQ ID NO:11) and

acetyl-KKKKKK.[BAT].GGPLYKKIIKKLLES (SEQ ID NO:12).

7. The composition of claim 6, having the formula:

acetyl-KKKKKCGCGGPLYKKIIKKLLES (SEQ ID NO:12).

8. The composition of claim 7, wherein the polysulfated glycan is heparin.

9. The composition of claim 1, wherein the polysulfated glycan is heparin, heparan sulfate, dextran sulfate, chondroitin sulfate, dermatan sulfate or a derivative thereof.

10. The composition of claim 1, wherein the technetium-99m binding moiety is selected from the group consisting of:

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

a technetium-99m bonding moiety comprising a single thiol moiety having a formula:

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 0or 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;

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

(amino acid)=any amino acid; ##STR6## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##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 or cyclic lower alkyl, aryl, heterocyclyl, a combination thereof or a substituted derivative thereof; ##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 or cyclic lower alkyl, aryl, heterocyclyl, a combination thereof or a substituted derivative 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.

11. The composition of claim 1, wherein the polybasic compound and the technetium-99m binding moiety are covalently linked through from about one to about twenty amino acids.

12. The composition of claim 10, wherein the technetium-99m binding moiety is Cp(aa)Cp and Cp is a protected cysteine having a protecting group of formula

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

13. The composition of claim 10, wherein the technetium-99m-binding moiety has a formula: ##STR9##

14. A kit for preparing a radiopharmwoutical preparation, said kit comprising a) a fist sealed vial containing a predetermined quantity of a reagent comprising:

i) a polybasic compound having a molecular weight from about 500 daltons to about 15,000 daltons and having at least 5 chemical functionalities that are basic at physiological pH;

ii) a technetium-99m binding moiety covalently linked to the compound; and

iii) a sufficient amount of a reducing agent to label the reagent with technetium-99m; and

b) a second sealed vial containing a predetermined quantity of a polysulfated glycan having a molecular weight of at least about 1,000 daltons.

15. The kit of claim 14, wherein the reducing agent is selected from the group of a dithionite ion, a stannous ion, and a ferrous ion.

16. The kit of claim 14, wherein the reagent is acetyl-KKKKKCGCGGPLYKIIKKLLES (SEQ ID NO:12) and the polysulfated glycan is heparin.

17. The composition of claim 1, further comprising technetium-99m.

18. A method of imaging a site of inflammation within a mammalian body comprising the steps of administering an effective diagnostic amount of the composition of claim 17 and detecting a radioactive signal from the Tc-99m localized at said site.

19. The method of claim 18, wherein the polybasic compound is acetyl-KKKKKCGCGGPLYKKIILLES (SEQ ID NO:12) and the polysulfated glycan is heparin.

20. A method of imaging a site of inflammation within a mammalian body comprising the steps of:

a) mixing whole blood and from about 1 microgram to 100 milligrams of the composition of claim 17 to form a radiolabeled mixture;

b) administering said mixture to a mammal; and

c) detecting a radioactive signal from the technetium-99m localized at said site.

21. The method of claim 20, wherein the polybasic compound is acetyl-KKKKKCGCGGPLYKKIIKKLLES (SEQ ID NO:12) and the polysulfated glycan is heparin.

22. A process for preparing a reagent comprising:

i) a polybasic compound having a molecular weight from about 500 daltons to about 15,000 daltons and having at least 5 chemical functionalities that are basic at physiological pH; and

ii) a technetium-99m binding moiety covalently linked to the compound; by in vitro chemical synthesis.

23. The process of claim 22, wherein the polybasic compound is a peptide and the synthesis is solid phase peptide synthesis.

24. The process of claim 22, wherein the technetium-99m binding moiety is covalently linked to the peptide during solid phase peptide synthesis.

25. The composition of claim 6, further comprising technetium-99m.

26. The composition of claim 6, further comprising technetium-99m.

27. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically-acceptable carrier.

28. A pharmaceutical composition comprising the composition of claim 8 and a pharmaceutically-acceptable carrier.

29. A composition comprising:

a) a multimeric reagent comprising

i) at least two polybasic compounds, each having a molecular weight from about 500 daltons to about 15,000 daltons and having at least 5 chemical functionalities that are basic at physiological pH,

ii) a technetium-99m binding moiety covalently linked to each compound; and

iii) a polyvalent linking moiety covalently linked to each compound and to each technetium-99m binding moiety; and

b) a polysulfated glycan having a molecular weight of at least about 1,000 daltons.

30. The composition of claim 29, wherein the polyvalent linking moiety is bis-succinimidylmethylether, 4-(2,2-dimethylacetyl)benzoic acid, N-[2-(N'N'-bis(2-succinimdo-ethyl)aminoethyl)]-N.sup.6,N.sup.9 -bis(2-methyl-2-mercaptopropyl)-6,9-diazanonanamide, tris(succinimidylethyl)amine, bis-succinimidohexane, 4-(O--H.sub.2 CO-Gly-Gly-Cys.amide)acetophenone, tris(acetamidoethyl)amine, bis(acetamidomethyl)amine, bis(acetamidoethyl)amine, .alpha.,.epsilon.-bis(acetyl)lysine, lysine, 1,8-bis-acetamido-3,6-dioxa-octane, a derivative of bis-succinimidylmethylether, a derivative of 4-(2,2-direthylacetyl)benzoic acid, a derivative of N-[2-(N',N'-bis(2-succinimido-ethyl)aminoethyl)]-N.sup.6,N.sup.9 -bis(2-methyl-2-mercaptopropyl)-6,9-diazanonanamide, a derivative of tris(succinimidylethyl)amine, bis-succinimidohexane, a derivative of 4-(O--CH.sub.2 CO-Gly-Gly-Cys.amide)acetophenone, a derivative of tris(acetamidoethyl)amine, a derivative of bis(acetamidomethyl)amine, a derivative of bis(acetamidoethyl)amine, a derivative of .alpha.,.epsilon.-bis(acetyl)lysine, a derivative of lysine, or a derivative of 1,8-bis-acetamido-3,6dioxa-octane.
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