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Details for Patent: 5,561,220

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Details for Patent: 5,561,220

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 specifically binding to 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: Diatech, Inc. (Londonderry, NH)
Filing Date:Jun 07, 1993
Application Number:08/073,577
Claims:1. A composition that is a scintigraphic imaging agent for imaging sites of inflammation within a mammalian body, the composition comprising a reagent comprised of a polybasic compound having a molecular weight of about 500 daltons to about 15,000 daltons and having at least 5 chemical functionalities that are basic at physiological pH, covalently linked to a technetium-99m binding moiety, the composition further comprising a polysulfated glycan having a molecular weight of about 1,000 daltons to about 60,000 daltons, wherein the reagent is radioactively labeled with technetium-99m, and wherein the composition is capable of binding to sites of inflammation in vivo.

2. The composition of claim 1 wherein the polybasic compound of the reagent comprising the composition is a peptide of 5 to 100 amino acids that is platelet factor 4 or a fragment thereof.

3. The composition of claim 1 wherein the polysulfated glycan is heparin, heparan sulfate, dextran sulfate, chondroitin sulfate, dermitan sulfate or derivatives thereof.

4. The composition of claim 1 wherein the technetium-99m binding moiety is 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=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.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, 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.

5. The composition of claim 1 wherein the polybasic compound and the radiolabel binding moiety are covalently linked through from about one to about twenty amino acids.

6. The composition of claim 4 wherein the protected cysteine of the radiolabel-binding moiety comprising the reagent of the composition 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.

7. The composition of claim 4 wherein the radiolabel-binding moiety of formula Cp(aa)Cp that comprises the reagent of the composition has the formula: ##STR8##

8. The composition of claim 2 wherein the polybasic compound comprising the reagent of the composition is a peptide having an amino acid sequence comprising the sequence PLYKKIIKKLLES or KKIIKKLLES.

9. The composition of claim 1 wherein the reagent further comprises a polyvalent linking moiety covalently linked to a multiplicity of the polybasic compounds and also covalently linked to a multiplicity of the technetium-99m 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.

10. The composition according to claim 9 comprising a multimeric polyvalent scintigraphic imaging agent wherein the polyvalent linking moiety is 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, bis-succinimidohexane, 4-(O-CH.sub.2 CO-Gly-Gly-Cys.amide)acetophenone or a derivative thereof.

11. An article of manufacture comprising a kit for preparing a radiopharmaceutical preparation, said kit comprising a first sealed vial containing a predetermined quantity of an unlabeled reagent comprising the composition according to claim 1 and a sufficient amount of reducing agent to label the reagent with technetium-99m.

12. The article of manufacture of claim 11, wherein the reducing agent in the first sealed vial is selected from the group of a dithionite ion, a stannous ion, or a ferrous ion.

13. The article of manufacture of claim 11 comprising a second sealed vial containing a predetermined quantity of the polysulfated glycan, wherein the composition of claim 1 is made by labeling the quantity in the first vial with technetium-99m and then mixing the contents of the first vial with the contents of the second vial.

14. The article of manufacture of claim 13, wherein the unlabeled reagent and the polysulfated glycan are contained in a single vial.

15. A process of preparing the reagent comprising the composition of claim 1 wherein the reagent is chemically synthesized in vitro.

16. The process of preparing the reagent according to claim 15 wherein the polybasic compound is a peptide and the peptide is synthesized by solid phase peptide synthesis.

17. The composition of claim 2 wherein the radiolabel binding moiety is covalently linked to the peptide during in vitro chemical synthesis.

18. The composition of claim 17 wherein the radiolabel binding moiety is covalently linked to the peptide during solid phase peptide synthesis.

19. A composition of matter having the formula:

20. The composition of matter of claim 19 that is labeled with technetium-99m.

21. A composition comprising the composition of matter of claim 19 and a polysulfated glycan.

22. The composition of claim 21 that is labeled with technetium-99m.
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