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|Title:||Technetium-99M labeled peptides for imaging inflammation|
|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. (Flagstaff, AZ)|
|Assignee:||Diatide, Inc. (Londonderry, NH)|
|Filing Date:||Jul 29, 1997|
|Claims:||1. A technetium-99m complex of a reagent comprising |
a) a glycoprotein IIb/IIIa receptor-binding compound having a molecular weight of less than 10,000 daltons; and
b) a radiolabel binding moiety covalently linked to the compound; wherein the reagent binds to a platelet glycoprotein IIb/IIIa receptor with sufficient affinity that said reagent inhibits adenosine diphosphate-induced aggregation of human platelets by 50%, in a standard platelet aggregation assay, when the reagent is present at a concentration of no more than 0.3 .mu.M.
2. The complex of claim 1, wherein compound is a peptide comprising 4 to 100 amino acids.
3. The complex of claim 2, wherein the radiolabel binding 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; a technetium-99m binding moiety comprising a single thiol moiety having a formula:
A is H, HOOC, H.sub.2 NOC, (peptide)--NHOC, (peptide)--OOC or R.sup.4 ;
B is H, SR, --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;
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;
and wherein the thiol moiety is in the reduced form; ##STR7## wherein X.dbd.H or a protecting group;
(amino acid)=any amino acid; ##STR8## wherein X.dbd.H or a protecting group;
(amino acid)=any amino acid; ##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, or heterocyclyl, a combination thereof; ##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, or heterocyclyl, a combination thereof;
V.dbd.H or --CO-peptide;
R.sup.6 .dbd.H or peptide;
and wherein when V.dbd.H, R.sup.6 =peptide and when R.sup.6 .dbd.H, V.dbd.--CO-peptide.
4. The complex of claim 1, wherein the peptide and the radiolabel binding moiety are covalently linked through from one to twenty amino acids.
5. The complex of claim 1, wherein the peptide is selected from the group consisting of: ##STR11##
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