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:
- Cp(aa)Cp I.
- wherein Cp is a protected cysteine and (aa) is an amino acid;
- A-CZ(B)-[C(R.sup.1 R.sup.2)].sub.n -X II.
- 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
- --CH.sub.2 --NH--CO--R
- 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:
- CH.sub.2 CO--Y.sub.D ApcGDCGGGC.sub.Acm GC.sub.Acm amide.
- 25.
- 25. A compound having the formula: ##STR16## wherein Boc represents a tert-butoxycarbonyl group
- and
- Trt represents a triphenylmethyl group.
Parent Case Info
This is a continuation of application Ser. No. 08/044,825, filed Apr. 8, 1993, which is a continuation-in-part of Ser. No. 07/653,012, filed Feb. 8, 1991, both now abandoned.
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Continuations (1)
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44825 |
Apr 1993 |
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Continuation in Parts (1)
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653012 |
Feb 1991 |
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