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Details for Patent: 6,056,940

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Details for Patent: 6,056,940

Title: Radiolabeled 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): McBride; William (Summit, NJ), Dean; Richard T. (Bedford, NH), Lister-James; John (Bedford, NH), Civitello; Edward R. (Bradford, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:Jan 11, 1996
Application Number:08/535,170
Claims:1. A reagent for preparing a thrombus imaging agent comprising, in

combination, a technetium-99m complexing moiety covalently linked to a platelet glycoprotein IIb/IIIa receptor binding moiety having a molecular weight of less than 10,000 daltons, wherein the reagent inhibits human platelet aggregation in platelet-rich plasma by 50% (IC.sub.50) when the reagent is present at a concentration of no more than 0.3 .mu.M.

2. The reagent of claim 1, wherein the receptor binding moiety is a peptide comprising from 4 to 100 amino acids.

3. The reagent of claim 1, wherein the technetium-99m complexing moiety has 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; ##STR7## wherein X=H or a protecting group; (amino acid)=any primary .alpha.- or .beta.-amino acid not containing a thiol group; ##STR8## wherein X=H or a protecting group; (amino acid)=any primary .alpha.- or .beta.-amino acid not containing a thiol group; ##STR9## 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; and ##STR10## 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.

4. The reagent of claim 2, wherein the peptide and the technetium-99m complexing moiety are covalently linked through one or more amino acids.

5. The reagent of claim 3, wherein the technetium-99m complexing moiety has the formula

and Cp comprises a protecting group having a 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.

6. The reagent of claim 3, wherein the technetium-99m complexing moiety has the formula: ##STR11##

7. A scintigraphic imaging agent comprising the reagent of claim 1, wherein the technetium-99m complexing moiety is complexed with technetium-99m.

8. The reagent of claim 2, wherein the peptide is selected from the group consisting of:

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

10. The complex of claim 9, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion, and a ferrous ion.

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

12. A process of preparing the reagent of claim 2 by chemical in vitro synthesis.

13. The process of claim 12, wherein the synthesis is solid phase peptide synthesis.

14. A method of labeling the reagent of claim 1, comprising the step of reacting the reagent with technetium-99m in the presence of a reducing agent.

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

16. The reagent of claim 2, wherein the peptide comprises a cyclic domain having a formula: wherein A is a lipophilic D-.alpha.-amino acid, an N-alkyl-L-.alpha.-amino acid or L-proline;

X is an L-.alpha.-amino acid having a positively charged sidechain; and

R is each independently H, lower alkyl or lower alkoxyalkyl.

17. The reagent of claim 16, wherein A is D-tyrosine or D-phenylalanine and X is L-{S-(3-aminopropyl)cysteine} or L-4-amidinophenylalanine.

18. The reagent of claim 1, wherein the technetium-99m complexing moiety comprises a single thiol-containing moiety of 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(.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 H or R.sup.4 ;

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

n is 0, 1, or 2;

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

19. The reagent of claim 18, wherein the technetium-99m complexing moiety is selected from the group consisting of:

-(amino acid).sup.1 -(amino acid).sup.2 -{A-CZ(B)-(C(R.sup.1 R.sup.2)).sub.n -X},

-{ A-CZ(B)-(C(R.sup.1 R.sup.2)).sub.n -X}-(amino acid).sup.1 -(amino acid).sup.2,

-(a primary .alpha.,.omega.- or .beta.,.omega.-diamino acid)-(amino acid).sup.1 -{A-CZ(B)-(C(R.sup.1 R.sup.2)).sub.n -X} and

-{A-CZ(B)-(C(R.sup.1 R.sup.2)).sub.n -X}-(amino acid).sup.1 -(a primary .alpha.,.omega.- or .beta.,.omega.-diamino acid).

20. A reagent for preparing a thrombus imaging agent comprising:

a) a polyvalent linker;

b) at least two platelet glycoprotein IIb/IIIa receptor binding compounds, each compound being covalently linked to the linker; and

c) at least two radiolabel complexing moieties, each moiety being covalently linked to the linker;

said reagent having a molecular weight of less than about 20,000 daltons;

wherein the reagent inhibits human platelet aggregation in platelet-rich plasma by 50% (IC.sub.50) when the reagent is present at a concentration of no more than 0.3 .mu.M.

21. The reagent of claim 20, wherein the linker is bis-succinimidylmethylether, 4-(2,2-dimethylacetyl)benzoic acid, N-[2-(N',N'bis(2-succinimidoethyl)aminoethyl)]-N.sup.6,N.sup.9 -bis(2-methyl-2-mercaptopropyl)-6,9-diazanonamide, tris(succinimidylethyl)amine, tris(2-chloroacetamidoethyl) amine, or 1,2-bis(2-chloroacetamidoethoxy)ethane.

22. A method of imaging a thrombus within a mammalian body comprising the steps of:

a) administering an effective diagnostic amount of the agent of claim 7 to said body; and

b) detecting technetium-99m accumulated at the thrombus.

23. A composition comprising a reagent having a formula: ##STR12##

24. A composition comprising a reagent having a formula:

25. A composition comprising a reagent having a formula:
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