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Last Updated: March 28, 2024

Details for Patent: 5,871,711


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Title: Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses
Abstract:This invention relates to therapeutic reagents and peptides, radiodiagnostic reagents and peptides, and methods for producing labeled radiodiagnostic agents. Specifically, the invention relates to peptide derivatives and analogs of somatostatin, and embodiments of such peptides labeled with technetium-99m (Tc-99m), as well as methods and kits for making, radiolabeling and using such peptides to image sites in a mammalian body. The invention also relates to peptide derivatives and analogues of somatostatin labeled with rhenium-186 (.sup.186 Re) and rhenium-188 (.sup.188 Re), and methods and kits for making, radiolabeling and using such peptides therapeutically in a mammalian body.
Inventor(s): Dean; Richard T. (Bedford, NH), Lister-James; John (Bedford, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:Jan 13, 1995
Application Number:08/347,397
Claims:1. A composition comprising a biologically active, isolated and purified homogeneous preparation of a peptide having a formula: ##STR7## wherein R.sup.1 and R.sup.2 are independently H, lower alkyl or substituted alkyl, aryl or substituted aryl;

R.sup.3 and R.sup.4 are each independently H, lower alkyl or substituted alky, aryl or substituted aryl, or either R.sup.3 or R.sup.4 are N(R.sup.10).sub.2, where each R.sup.10 is independently H, lower alkyl or a peptide sequence of no more than 10 amino acids, and m is an integer between 0 and 3;

X.sup.1 and X.sup.2 are each independently a D- or L- amino acid, and n and q are independently either 0 or 1;

A.sup.1 is D-Phe, L-Phe, D-Tyr, L-Tyr, Nal, or a substituted derivative thereof;

A.sup.2 is D-Trp, L-Trp, or a substituted derivative thereof;

A.sup.3 is D-Lys, L-Lys, Hly, Achxa, Amf, Aec, Apc, Aes, or Aps;

A.sup.4 is Thr, Ser, Val, Phe, Ile, Abu, Nle, Leu, Nva or Aib;

X.sup.3 is H, --COOR.sup.9, --CH.sub.2 OH, CH.sub.2 COOR.sup.9, or --CON(R.sup.9).sub.2, where each R.sup.9 is independently H, lower linear or cyclic alkyl, or a peptide sequence of no more than 10 amino acid residues;

R.sup.5 and R.sup.6 are each independently H or lower alkyl and p is either 0, 1 or 2;

and R.sup.7 and R.sup.8 are independently H, lower alkyl or substituted lower alkyl, or either R.sup.7 or R.sup.8 are --COOH or --COOR.sup.1 or COONR.sup.1.sub.2 ;

wherein said peptide binds to a somatostatin receptor.

2. The composition of claim 1 further comprising a pharmaceutically acceptable carrier.

3. A reagent comprising a peptide having a formula: ##STR8## wherein R.sup.1 and R.sup.2 are independently H, lower alkyl or substituted alky, aryl or substituted aryl;

R.sup.3 and R.sup.4 are each independently H, lower alkyl or substituted alkyl, aryl or substituted aryl, or either R.sup.3 or R.sup.4 are N(R.sup.10).sub.2, where each R.sup.10 is independently H, lower alkyl or a peptide sequence of no more than 10 amino acids, and m is an integer between 0 and 3;

X.sup.1 and X.sup.2 are each independently a D- or L- amino acid, and n and q are independently either 0 or 1;

A.sup.1 is D-Phe, L-Phe, D-Tyr, L-Tyr, Nal, or a substituted derivative thereof;

A.sup.2 is D-Trp, L-Trp, or a substituted derivative thereof:

A.sup.3 is D-Lys, L-Lys, Hly, Achxa, Amf, Aec, Apc, Aes, or Aps;

A.sup.4 is Thr, Ser, Val, Phe, Ile, Abu, Nle, Leu, Nva or Aib;

X.sup.3 is H, --COOR.sup.9, --CH.sub.2 OH, CH.sub.2 COOR.sup.9, or --CON(R.sup.9).sub.2, where each R.sup.9 is independently H, lower linear or cyclic alkyl, or a peptide sequence of no more than 10 amino acid residues,

R.sup.5 and R.sup.6 are each independently H or lower alkyl and p is either 0, 1 or 2;

and R.sup.7 and R.sup.8 are independently H, lower alkyl or substituted lower alky, or either

R.sup.7 or R.sup.8 are --COOH or --COOR.sup.1 or COONR.sup.1.sub.2,

wherein said peptide binds to a somatostatin receptor; and a technetium-99m binding moiety covalently linked to the peptide, the moiety having a formula selected from the group consisting of:

I.

wherein (pgp).sup.s is H or a thiol protecting group and (aa) is an amino acid;

II. said technetium-99m binding moiety comprising a single thiol containing moiety having a formula

wherein

A is H, HOOC, H.sub.2 NOC, (peptide)-NHOC, (peptide)-OOC or R"";

B is H, SH, --NHR"', --N(R"')-(peptide), or R"";

X is H, SH, --NHR"', --N(R"')-(peptide) or R"";

Z is H or R"";

R', R", R"' and R"" are independently H or lower straight or branched chain or cyclic alkyl;

n is 0, 1 or2;

and

where B is --NHR"' or --N(R"')-(peptide), X is SH, and n is 1 or 2;

where X is --NHR"' or --N(R"')-(peptide), B is SH, and n is 1 or 2;

where B is H or R"", 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"", then where B is SH, X is --NHR"' or --N(R"')-(peptide) and where X is SH, B is --NHR"' or --N(R"')-(peptide);

where X is H or R"", 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; ##STR9## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##STR10## wherein X=H or a protecting group;

(amino acid)=any amino acid; ##STR11## wherein each R 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, a combination thereof or a substituted derivative thereof; and ##STR12## wherein each R is independently H, CH.sub.3 or C.sub.2 H.sub.5 ;

m, n and p are independently 2 or 3;

A=linear or cyclic lower alkyl, aryl, heterocyclyl, a combination thereof or a substituted derivative thereof;

V=H or --CO-peptide;

R'=H or peptide;

and wherein when V=H, R'=peptide and when R'=H, V=--CO-peptide.

4. The reagent of claim 3 further comprising technetium-99m complexed with the technetium-99m binding moiety.

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

and (pgp).sup.s has a formula

wherein R is a lower alkyl having 1 to 6 carbon atoms, a 2-pyridyl, a 3-pyridyl, a 4-pyridyl, a phenyl, or a phenyl substituted with a lower alkyl, a hydroxy, a lower alkoxy, a carboxy, or a lower alkoxycarbonyl.

6. The reagent of claim 3, wherein the technetium-99m binding moiety has a formula: ##STR13##

7. The reagent of claim 4, wherein a complex is formed by reacting the reagent with technetium-99m in the presence of a reducing agent.

8. The complex of claim 7, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion and a ferrous ion.

9. The reagent of claim 4, wherein a complex is formed by reacting the reagent with technetium-99m by ligand exchange of a prereduced technetium-99m complex.

10. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the reagent of claim 3 and a sufficient amount of a reducing agent to label the reagent with technetium-99m.

11. A method of labeling the reagent of claim 3 comprising the step of reacting the reagent with technetium-99m in the presence of a reducing agent.

12. The method of claim 11, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion and a ferrous ion.

13. A method for imaging a site within a mammalian body comprising the steps of administering an effective diagnostic amount of the reagent of claim 4 to the body and detecting the technetium-99m localized at the site.

14. The reagent of claim 3 wherein the peptide is chemically synthesized in vitro.

15. The reagent of claim 14 wherein the peptide is synthesized by solid phase peptide synthesis.

16. The reagent of claim 14 wherein the technetium-99m binding moiety is covalently linked to the peptide during in vitro chemical synthesis.

17. The reagent of claim 16 wherein the technetium-99m binding moiety is covalently linked to the peptide during solid phase peptide synthesis.

18. The composition of claim 1 wherein A.sup.1 is phenylalanine or tyrosine, A.sup.2 is tryptophan, A.sup.3 is lysine and A.sup.4 is threonine or valine.

19. A peptide selected from the group consisting of:

CH.sub.2 CO.YW.sub.D KTCTC.sub.Acm GC.sub.Acm.amide, (SEQ ID NO: 1);

CH.sub.2 CO.YW.sub.D KTC.amide, (SEQ ID NO:2);

CH.sub.2 CO.YW.sub.D KTCT(CH.sub.2 OH), (SEQ ID NO:3);

CH.sub.2 CO.YW.sub.D KTCTGGC.sub.Mob.amide, (SEQ ID NO:4);

CH.sub.2 CO.FFW.sub.D KTFC, (SEQ ID NO:5);

CH.sub.2 CO.FFW.sub.D KTFC.amide, (SEQ ID NO:5);

CH.sub.2 CO.FW.sub.D KTC.sub.D, (SEQ ID NO:8);

CH.sub.2 CO.FW.sub.D KT.Hcy, (SEQ ID NO:7);

CH.sub.2 CO.FW.sub.D KT.Hcy.amide, (SEQ ID NO:7);

CH.sub.2 CO.FW.sub.D KT.Pen, (SEQ ID NO:9);

CH.sub.2 CO.NFFW.sub.D KTFFC, (SEQ ID NO: 10);

CH.sub.2 CO.FFW.sub.D KTFCC.sub.Acm GC.sub.Acm.amide, (SEQ ID NO: 11);

CH.sub.2 CO.FFW.sub.D KTF.Hcy, (SEQ ID NO: 12);

PhCH.sub.2 CHCO.YW.sub.D KTC, (SEQ ID NO:3);

CH.sub.2 CO.YW.sub.D KT.Hhc, (SEQ ID NO:13);

CH.sub.2 CO.YW.sub.D KT.Hhc.amide, (SEQ ID NO: 13);

CH.sub.2 CO.FFW.sub.D KTF.Hhc, (SEQ ID NO: 14);

and

CH.sub.2 CO.FYW.sub.D KTFC, (SEQ ID NO: 15).

20. A method for alleviating a somatostatin-related disease in an animal comprising the step of administering to the animal an effective therapeutic amount of the composition of claim 1.

21. A method for alleviating a somatostatin-related disease in an human comprising the step of administering to the human an effective therapeutic amount of the composition of claim 1.

22. The method of claim 20, wherein from about 0.1 to about 49 mg/kg body weight/day of the peptide is administered to the animal.

23. A reagent for preparing a radiolabeled somatostatin receptor-binding agent comprising the composition of claim 1, wherein a radiolabel-binding moiety is covalently linked to the peptide.

24. A radiolabeled somatostatin receptor binding agent comprising the reagent of claim 23 and .sup.186 Re or .sup.188 Re.

25. A complex formed by reacting the reagent of claim 23 with .sup.186 Re or .sup.188 Re in the presence of a reducing agent.

26. The complex of claim 25, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion and a ferrous ion.

27. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the reagent of claim 23 and a sufficient amount of a reducing agent to label the reagent with .sup.186 Re or .sup.188 Re.

28. The reagent of claim 23 wherein the peptide is chemically synthesized in vitro.

29. The reagent of claim 28 wherein the peptide is synthesized by solid phase peptide synthesis.

30. The reagent of claim 28 wherein the radiolabel-binding moiety is covalently linked to the peptide during in vitro chemical synthesis.

31. The reagent of claim 30 wherein the radiolabel-binding moiety is covalently linked to the peptide during solid phase peptide synthesis.

32. A pharmaceutical composition comprising the agent of claim 24 and a pharmaceutically acceptable carrier.

33. A method for alleviating a somatostatin-related disease in an animal comprising the step of administering to the animal an effective therapeutic amount of the composition of claim 32.

34. The method of claim 33 wherein the animal is a human.

35. The method of claim 33, wherein from about 10 to 200 milliCuries of the radiolabeled composition is administered to the animal.

36. The reagent of claim 23 further comprising technetium-99m.

37. A pharmaceutical composition comprising the reagent of claim 36, and a pharmaceutically acceptable carrier.

38. A complex formed by reacting the reagent of claim 23 with technetium-99m in the presence of a reducing agent.

39. The complex of claim 38, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion and a ferrous ion.

40. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the reagent of claim 23 and a sufficient amount of a reducing agent to label the reagent with technetium-99m.

41. A method for imaging a site within a mammalian body comprising administering a diagnostically effective amount of a radiolabeled somatostatin receptor binding peptide of claim 37 and detecting the radiolabel localized at the site in the mammalian body.

42. The composition of claim 1 further comprising a polyvalent linking moiety having at least two functional groups capable of covalently bonding to the peptide or a radiolabel binding moiety.

43. The composition of claim 42 wherein the polyvalent liking moiety 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-diazanonanamide, tris(succinimidyl-ethyl)amine or a derivative thereof.

44. The reagent of claim 3 further comprising a polyvalent linking moiety having at least two functional groups capable of covalently bonding to the peptide or a radiolabel binding moiety.

45. The reagent of claim 44 wherein the polyvalent linking moiety 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-diazanonanamide, tris(succinimidylethyl)amine or a derivative thereof.

46. The complex of claim 38 wherein the complex of the radiolabel-binding moiety and technetium-99m is electrically neutral.

47. The reagent of claim 19 further comprising technetium-99m.

48. The reagent of claim 19 further comprising .sup.186 Re or .sup.188 Re.

49. The method of claim 21, wherein from about 0.1 to about 49 mg/kg body weight/day is administered to the animal.

50. The method of claim 34, wherein from about 10 to 200 milliCuries of the radiolabeled peptide is administered to the human.

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