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Details for Patent: 6,074,627

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Details for Patent: 6,074,627

Title: Technetium-99m labeled peptides for imaging
Abstract:This invention relates to radiolabeled peptides and methods for producing such peptides. Specifically, the invention relates to peptides, methods and kits for making such peptides, and methods for using such peptides to image sites in a mammalian body labeled with technetium-99m (Tc-99m) via a radiolabel-binding moiety covalently attached to a specific binding peptide via an amino acid side-chain of the peptide.
Inventor(s): Dean; Richard T. (Bedford, NH), Buttram; Scott (Derry, NH), McBride; William (Manchester, NH), Lister-James; John (Bedford, NH), Civitello; Edgar R. (Londonderry, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:May 14, 1996
Application Number:08/582,134
Claims:1. A stable technetium complex of a reagent comprising:

a) a peptide comprising between 3 and 100 amino acids that specifically binds to a target site in a mammalian body; and

b) a technetium-99m complexing moiety covalently linked to a sidechain of an amino acid of the peptide, said moiety having 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; ##STR6## wherein X=H or a protecting group;

(amino acid)=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 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;

X=peptide;

and ##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 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 =said sidechain and when R.sup.6 =H, V=--CO-said sidechain.

2. A stable technetium-99m complex of a reagent comprising:

a) a peptide comprising between 3 and 100 amino acids that specifically binds to a target site in a mammalian body; and

b) a technetium-99m complexing moiety covalently linked to a sidechain of an amino acid of the peptide, said moiety having a formula

wherein Cp is a protected cysteine and (aa) is any primary .alpha.- or .beta.-amino acid not containing a thiol group

and wherein the cysteine is protected by

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.

3. The complex of claim 2, wherein the moiety has the formula: ##STR10##

4. A scintigraphic imaging agent comprising the complex of claim 1.

5. A stable technetium-99m complex of a reagent comprising: a) a peptide comprising between 3 and 100 amino acids that specifically binds to a target site in a mammalian body; and

b) a technetium-99m complexing moiety covalently linked to a sidechain of an amino acid of the peptide, wherein the 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.

6. The complex of claim 5, wherein the 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.

7. A scintigraphic imaging agent comprising the complex of claim 5.

8. A stable technetium-99m complex of a reagent comprising

a) a peptide selected from the group consisting of:

formyl-MLF

(VGVAPG).sub.3 amide;

(VPGVG).sub.4 amide;

RALVDTLKFVTQAEGAKamide (SEQ ID No.:1);

RALVDTEFKVKQEAGAKamide (SEQ ID No.:2);

PLARITLPDFRLPEIAIPamide (SEQ ID No.:3);

GQQHHLGGAKAGDV (SEQ ID No.:4);

PLYKKIIKKLLES (SEQ ID No.:5);

LRALVDTLKamide (SEQ ID No.:6);

GGGLRALVDTLKamide (SEQ ID No.:7);

GGGLRALVDTLKFVTQAEGAKamide (SEQ ID No.:8);

GGGRALVDTLKALVDTLamide (SEQ ID No.:9);

GHRPLDKKREEAPSLRPAPPPISGGGYR (SEQ ID No.:10);

PSPSPIHPAHHKRDRRQamide (SEQ ID No.:11);

GGGF.sub.D.Cpa.YW.sub.D KTFTamide; ##STR11## (SYNRGDSTC).sub.3 -TSEA GGGLRALVDTLKamide (SEQ ID No.:13);

GCGGGLRALVDTLKamide (SEQ ID No.:14);

GCYRALVDTLKFVTQAEGAKamide (SEQ ID No.:15); and

GC(VGVAPG).sub.3 amide; and

b) a technetium-99m complexing moiety covalently linked to a sidechain of an amino acid of the peptide.

9. A stable technetium-99m complex of a reagent comprising:

a) a peptide comprising between 3 and 100 amino acid residues that specifically binds to a target site in a mammalian body, wherein one of said residues has a thiol sidechain; and

b) a technetium-99m complexing moiety covalently linked to said sidechain,

wherein the complex accumulates at the target site when injected into said body.

10. A stable technetium-99m complex of a reagent comprising:

a) at least two copies of a peptide comprising between 3 and 100 amino acid residues that specifically binds to a target site in a mammalian body, wherein one of said residues has a thiol sidechain;

b) a technetium-99m complexing moiety covalently linked to each thiol sidechain;

c) a polyvalent linker covalently linked to the peptides or to the moieties;

wherein the complex accumulates at the target site when injected into said body.

11. The complex of claim 10, wherein the polyvalent linker is selected from the group consisting of 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.

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

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

14. The complex of claim 9, formed by reacting the reagent with technetium-99m by ligand exchange of a prereduced technetium-99m complex.

15. The complex of claim 9, wherein the peptide and the moiety is a cyclic peptide.

16. The complex of claim 9, wherein the peptide and the moiety are linked through a homocysteine residue.

17. A scintigraphic imaging agent comprising the complex of claim 9.
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