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Claims for Patent: 5,645,815

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Claims for Patent: 5,645,815

Title: Radiolabled compounds for thrombus imaging
Abstract:This invention relates to radiolabeled scintigraphic imaging agents, and methods and reagents for producing such agents. Specifically, the invention relates to specific binding compounds, including peptides, that bind to a platelet receptor that is the platelet GPIIb/IIIa receptor, methods and kits for making such compounds, and methods for using such compounds labeled with technetium-99m via a covalently-linked radiolabel-binding moiety to image thrombi in a mammalian body.
Inventor(s): Dean; Richard T. (Bedford, NH), Lister-James; John (Bedford, NH), Civitello; Edgar R. (Bradford, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Application Number:08/439,905
Patent Claims: 1. A reagent for preparing a thrombus imaging agent for imaging thrombi within a mammalian body, comprising, in combination, a radiolabel binding moiety that is capable of binding technetium-99m, indium-111 or gallium-68, and that is covalently linked to a specific binding compound that is less than 10,000 daltons in molecular weight and that binds to a platelet glycoprotein IIb/IIIa receptor, wherein the reagent inhibits human platelet aggregation in platelet-rich plasma by 50% (IC.sub.50) when present at a concentration of no more than 0.3 .mu.M.

2. A reagent according to claim 1 wherein the specific binding compound is a peptide of 4 to 100 amino acids.

3. The reagent of claim 1 wherein the radiolabel binding moiety has a 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 --NCR.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 ##STR7## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##STR8## 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; ##STR9## 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.

4. The reagent of claim 1 wherein the specific binding peptide and the radiolabel binding moiety are covalently linked through one or more amino acids.

5. The reagent of claim 3 wherein the protected cysteine of the radiolabel-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.

6. The reagent of claim 3 wherein the radiolabel-binding moiety of formula Cp(aa)Cp has the formula: ##STR10##

7. A scintigraphic imaging agent comprising the reagent according to claim 1 wherein the radiolabel binding moiety is bound to a radiolabel.

8. The reagent of claim 2 wherein the specific binding peptide is selected from the group consisting of peptides having the amino acid sequence: ##STR11##

9. The reagent of claim 1 wherein the reagent further comprises a polyvalent linking moiety covalently linked to a multiplicity of specific binding compounds and also covalently linked to a multiplicity of radiolabel-binding moieties to comprise a reagent for preparing 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 reagent of claim 9 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 or a derivative thereof.

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

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

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

14. 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.

15. A method for imaging thrombi within a mammalian body comprising administering an effective diagnostic amount of the reagent of claim 2 that is labeled with technetium-99m and detecting the Tc-99m localized at the site of the thrombus.

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 reagent according to claim 1 having the formula: ##STR12##

21. A reagent according to claim 1 having the formula: ##STR13##

22. A reagent according to claim 1 having the formula: ##STR14##

23. A reagent according to claim 1 having the formula: ##STR15##

24. A reagent according to claim 1 having the formula:

25.

25. A compound having the formula: ##STR16## wherein Boc represents a tert-butoxycarbonyl group

and

Trt represents a triphenylmethyl group.
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