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Details for Patent: 5,830,856

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Details for Patent: 5,830,856

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): Dean; Richard T. (Bedford, NH), Lister-James; John (Bedford, NH), Civitello; Edgar R. (Bradford, NH), McBride; William (Manchester, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:Jun 03, 1994
Application Number:08/253,317
Claims:1. A reagent for preparing a thrombus imaging agent, comprising a radiolabel complexing moiety covalently linked to a compound having a molecular weight of less than 10,000 daltons, wherein the compound specifically binds to platelet glycoprotein IIb/IIIa receptor, and wherein the reagent is capable of inhibiting human platelet aggregation in platelet-rich plasma by 50% (IC.sub.50) when present at a concentration not greater than about 1 .mu.M.

2. The reagent of claim 1 wherein the compound is a platelet glycoprotein IIb/IIIa receptor binding peptide having from 4 to 100 amino acids.

3. The reagent of claim 1 wherein the radiolabel 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; and ##STR5## wherein X=H or a protecting group;

(amino acid)=any primary .alpha.- or .beta.-amino acid not containing a thiol group; ##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;

X=a platelet glycoprotein IIb/IIIa receptor binding compound; and ##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-- platelet glycoprotein IIb/IIIa receptor binding compound;

R.sup.6 =H or platelet glycoprotein IIb/IIIa receptor binding compound;

and wherein when V=H, R.sup.6 =platelet glycoprotein IIb/IIIa receptor binding compound and when R.sup.6 =H, V=--CO-- platelet glycoprotein IIb/IIIa receptor binding compound.

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

5. The reagent of claim 3 wherein the protected cysteine of 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 complexing moiety has the formula: ##STR8##

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

CH.sub.2 CO.Y.sub.D.Apc.GDCGGG

CH.sub.2 CO.Y.sub.D.Apc.GDCKG

CH.sub.2 CO.Y.sub.D.Apc.GDCGG

CH.sub.2 CO.Y.sub.D.Apc.GDC

CH.sub.2 CO.Y.sub.D.Apc.GDCK

CH.sub.2 CO.Y.sub.D.Amp.GDC

CH.sub.2 CO.Y.sub.D.Amp.GDCK

and O--(4-piperidinyl)butyl tyrosine.

8. A multimeric reagent for preparing a thrombus imaging agent comprising:

a polyvalent linker covalently linked to

a) at least two compounds that specifically bind to a platelet glycoprotein IIb/IIIa receptor; and

b) at least one radiolabel complexing moiety;

wherein the reagent has a molecular weight of less than about 20,000 daltons, and wherein the reagent is capable of inhibiting human platelet aggregation in platelet-rich plasma by 50 % (IC.sub.50) when present at a concentration not greater than about 1 .mu.M.

9. The reagent of claim 8 wherein the polyvalent linker 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, tris(acetamidoethyl)amine, bis-(acetamidoethyl)ether, bis-(acetamidomethyl)ether, .alpha.,.epsilon.-bisacetyllysine, lysine and 1,8-bis-acetamido-3,6-dioxa-octane. 1,2-bis(2-chloroacetamidoethoxy)ethane, or a derivative thereof.

10. A process for preparing the reagent of claim 2 wherein the peptide is chemically synthesized in vitro.

11. The process of claim 10 wherein the peptide is synthesized by solid phase peptide synthesis.

12. The reagent of claim 2 wherein the radiolabel complexing moiety is covalently linked to the peptide during in vitro chemical synthesis.

13. The reagent of claim 12 wherein the radiolabel complexing moiety is covalently linked to the peptide during solid phase peptide synthesis.

14. The reagent of claim 1, wherein the compound comprises a cyclic peptide platelet glycoprotein IIb/IIa receptor binding domain having the formula: ##STR9## wherein A is a lipophilic D-.alpha.-amino acid, or an N-alkyl-L-.alpha.-amino acid or L-proline;

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

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

15. The reagent of claim 14, wherein A is D-tyrosine or D-phenylalanine and X is L-(S-(3-aminopropyl)cysteine) or L-4-amidinophenylalanine.

16. The reagent of claim 1 wherein the radiolabel 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(R.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 or lower straight or branched chain or cyclic alkyl;

n is 0, 1 or 2;

(peptide) is a peptide of 2 to about 10 amino acids;

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(R.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 the thiol moiety is in the reduced form and (amino acid) is any primary .alpha.- or .beta.-amino acid not containing a thiol group.

17. The reagent of claim 16 wherein the radiolabel complexing moiety is selected from the group consisting of:

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

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

IIc. -(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}, or

IId. -{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)

wherein

(amino acid).sup.1 and (amino acid).sup.2 are each independently any naturally-occurring, modified, substituted or altered .alpha.- or .beta.-amino acid not containing a thiol group;

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 or --NHR.sup.3, --N(R.sup.3)-(amino acid or peptide) or R.sup.4 ;

X is SH or --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 or straight or branched chain or cyclic lower alkyl;

(peptide) is a peptide of 2 to about 10 amino acids;

n is an integer that is either 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(R.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, (peptide)--OOC and B is SH and n is 0;

and wherein the thiol moiety is in the reduced form.

18. A composition of matter having the formula:

19. A composition of matter comprising a cyclic peptide having a molecular weight of less than 10,000 daltons wherein the peptide specifically binds to a platelet glycoprotein IIb/IIIa receptor and is capable of inhibiting human platelet aggregation in platelet-rich plasma by 50 % (IC.sub.50) when present at a concentration not greater than about 1 .mu.M, wherein the peptide comprises the sequence -Amp-Gly-Asp-.

20. The composition of matter of claim 19, wherein the peptide comprises the formula: ##STR10## wherein A is a lipophilic D-.alpha.-amino acid, or an N-alkyl-L-.alpha.-amino acid or L-proline; and

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

21. The composition of matter of claim 19, selected from the group consisting of:

CH.sub.2 CO.Y.sub.D.Amp.GDC and

CH.sub.2 CO.Y.sub.D.Amp.GDCK.

22. A composition of matter selected from the group consisting of cyclic peptides having the formula:

CH.sub.2 CO.Y.sub.D.Apc.GDCGGG

CH.sub.2 CO.Y.sub.D.Apc.GDCKG

CH.sub.2 CO.Y.sub.D.Apc.GDCGG

CH.sub.2 CO.Y.sub.D.Apc.GDC

CH.sub.2 CO.Y.sub.D.Apc.GDCK

CH.sub.2.COY.sub.D GDC

CH.sub.2 CO.Y.sub.D.Amp.GDCK

and O--(4-piperidinyl)butyl tyrosine.

23. A composition of matter having the formula:
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