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Details for Patent: 6,017,509

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Details for Patent: 6,017,509

Title: Radiolabeled somatostatin receptor-binding peptides
Abstract:This invention relates to therapeutic reagents and peptides, including radiotherapeutic reagents and peptides, radiodiagnostic reagents and peptides, and methods for producing labeled radiodiagnostic agents. Specifically, the invention relates to cyclic peptide derivatives and analogs of somatostatin, and embodiments of such peptides radiolabeled with a radioisotope, as well as methods and kits for making, radiolabeling and using such peptides for radiodiagnostic and radiotherapeutic purposes. The invention specifically relates to cyclic peptide derivatives and analogues of somatostatin radiolabeled with technetium-99m and uses thereof as scintigraphic imaging agents. The invention also specifically relates to cyclic peptide derivatives and analogues of somatostatin radiolabeled with cytotoxic radioisotopes such as rhenium-186 (.sup.186 Re) and rhenium-188 (.sup.188 Re) for use as radiotherapeutic agents. Methods and kits for making, radiolabeling and using such peptides diagnostically and therapeutically in a mammalian body are also provided.
Inventor(s): Dean; Richard T. (Bedford, NH), McBride; William (Manchester, NH), Lister-James; John (Bedford, NH)
Assignee: Diatide, Inc. (Londonderry, NH)
Filing Date:Jul 15, 1993
Application Number:08/092,355
Claims:1. A reagent comprising:

a) a somatostatin receptor-binding peptide having a formula

wherein

B.sup.1 is D-Phe, L-Phe, D-Tyr, L-Tyr, D-Nal, L-Nal, or Ain;

B.sup.2 is D-Trp, or L-Trp;

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

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

C.sup.4 is an L-amino acid;

A.sup.4 is a lipophilic D-amino acid, a lipophilic L-(.alpha.-N-alkyl)amino acid, or L-proline;

wherein A.sup.4 and C.sup.4 are covalently linked through an amino terminus of A.sup.4 and a carboxyl terminus of C.sup.4 to form a cyclic peptide; and

b) a radiolabel-binding moiety covalently linked to C.sup.4.

2. The reagent of claim 1, wherein B.sup.1 is phenylalanine or tyrosine, B.sup.2 is D-tryptophan, B.sup.3 is lysine, and B.sup.4 is threonine or valine.

3. A composition comprising:

a) at least two copies of the reagent of claim 1; and

b) a polyvalent linker covalently linked to each peptide and to each radiolabel-binding moiety to form a multimer;

wherein the molecular weight of the multimer is less than about 20,000 daltons.

4. The composition of claim 3, 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-succinimidoethyl)aminoethyl)]-N.sup.6,N.sup.9 -bis(2-methyl-2-mercaptopropyl)-6,9-diazanonanamide, tris(succinimidylethyl)amine, and N-[2-(N',N'-bis(2-succinimidoethyl)aminoethyl)]-N.sup.6, N.sup.9 -bis(2-methyl-2-mercaptopropyl)-6,9-diazanonanamide.

5. A scintigraphic imaging agent comprising the reagent of claim 1 radiolabeled with technetium-99m.

6. A scintigraphic imaging agent comprising the reagent of claim 1 radiolabeled with indium-111, gallium-67 or gallium-68.

7. A radiotherapeutic agent comprising the reagent of claim 1 radiolabeled with a cytotoxic radioisotope selected from the group consisting of scandium-47, copper-67, gallium-72, yttrium-90, samarium-153, gadolinium-159, dysprosium-165, holmium-166, ytterbium-175, lutetium-177, rhenium-186, rhenium-188, and bismuth-212.

8. A complex formed by reacting the reagent of claim 1 with technetium-99m in the presence of a reducing agent.

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

10. A complex formed by labeling the reagent of claim 1 with technetium-99m by ligand exchange of a prereduced technetium-99m complex.

11. A composition comprising the reagent of claim 1 and a stannous ion.

12. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the reagent of claim 1 and a sufficient amount of a reducing agent to label the reagent with technetium-99m, rhenium-186, or rhenium-188.

13. A method of labeling the reagent of claim 1 comprising the step of reacting the reagent with technetium-99m in the presence of a reducing agent.

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

15. A method of imaging a site within a mammalian body comprising the steps of administering an effective diagnostic amount of the agent of claim 5; and detecting the technetium-99m localized at the site.

16. The reagent of claim 1, wherein the peptide is chemically synthesized in vitro.

17. The reagent of claim 16, wherein the peptide is synthesized by solid phase peptide synthesis.

18. The reagent of claim 16, wherein the radiolabel-binding moiety is covalently linked to the peptide during in vitro peptide synthesis.

19. The reagent of claim 18, wherein the radiolabel-binding moiety is covalently linked to the peptide during solid phase peptide synthesis.

20. The reagent of claim 1, wherein the radiolabel-binding moiety is selected from the group consisting of:

(a)

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

(b)

a radiolabel-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 or 2; 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, or (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, or (peptide)-OOC and B is SH;

where Z is methyl, X is methyl, A is HOOC, H.sub.2 NOC, (peptide)-NHOC, or (peptide)-OOC, B is SH and n is 0;

and wherein the thiol moiety is in the reduced form;

(c) ##STR29## wherein X=H or a protecting group;

(amino acid)=any amino acid;

(d) ##STR30## wherein X=H or a protecting group;

(amino acid)=any amino acid;

(e) ##STR31## 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, or a combination thereof; and

(f) ##STR32## 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, or combinations thereof;

V=H or --CO-peptide;

R'=H or peptide;

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

21. The reagent of claim 20 wherein the radiolabel-binding moiety has the formula

and (pgp).sup.S has a formula

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.

22. The reagent of claim 20, wherein the radiolabel-binding moiety has a formula: ##STR33##

23. A scintigraphic imaging agent comprising the reagent of claim 20 and technetium-99m.

24. A complex formed by reacting the reagent of claim 20 with technetium-99m in the presence of a reducing agent.

25. The complex of claim 24, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion and a ferrous ion.

26. A complex formed by labeling the reagent of claim 20 with technetium-99m by ligand exchange of a prereduced technetium-99m complex.

27. A composition comprising the reagent of claim 20 and a stannous ion.

28. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the reagent of claim 20 and a sufficient amount of a reducing agent to label the reagent with technetium-99m.

29. A method of labeling the reagent of claim 20 comprising the step of reacting the reagent with technetium-99m in the presence of a reducing agent.

30. The method of claim 29, wherein the reducing agent is selected from the group consisting of a dithionite ion, a stannous ion and a ferrous ion.

31. A method of imaging a site within a mammalian body comprising the steps of administering an effective diagnostic amount of the agent of claim 23 and detecting the technetium-99m localized at the site.

32. The reagent of claim 20, wherein the peptide is chemically synthesized in vitro.

33. The reagent of claim 32, wherein the peptide is synthesized by solid phase peptide synthesis.

34. The reagent according to claim 32 wherein the radiolabel-binding moiety is covalently linked to the peptide during in vitro chemical synthesis.

35. The reagent according to claim 34 wherein the radiolabel-binding moiety is covalently linked to the peptide during solid phase peptide synthesis.

36. A composition comprising: a) at least two copies of the reagent of claim 20; and

b) a polyvalent linker covalently linked to each peptide and to each radiolabel-binding moiety to form a multimer;

wherein the molecular weight of the multimer is less than about 20,000 daltons.

37. The composition of claim 36, 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-succinimidoethyl)aminoethyl)]-N.sup.6,N.sup.9 -bis(2-methyl-2-mercaptopropyl)-6,9-diazanonanamide, or tris(succinimidylethyl)amine.

38. A composition comprising a peptide having a formula selected from the group consisting of:

and

39.

39. A radiotherapeutic agent comprising the reagent of claim 20 radiolabeled with rhenium-186 or rhenium-188 in the presence of a reducing agent.

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

41. A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing a predetermined quantity of the reagent of claim 20 and a sufficient amount of a reducing agent to radiolabel the reagent with rhenium-186 or rhenium-188.

42. The composition of claim 38 radiolabeled with a radioisotope selected from the group consisting of gallium-68, technetium-99m, indium-111, and iodine-123.

43. The composition of claim 38 radiolabeled with a radioisotope selected from the group consisting of scandium-47, copper-67, gallium-72, yttrium-90, tin-117m, iodine-125, iodine-131, samarium-153, gadolinium-159, dysprosium-165, holmium-166, ytterbium-175, lutetium-177, rhenium-186, rhenium-188, astatine-211, and bismuth-212.

44. A method of alleviating a somatostatin-related disease in an animal comprising administering a therapeutically effective amount of the composition of claim 38 to the animal.

45. The method of claim 44 wherein the animal is a human.

46. A method of alleviating a somatostatin-related disease in an animal comprising the step of administering a therapeutically effective amount of the composition of claim 43 to the animal.

47. The method of claim 46 wherein the animal is a human.

48. The method of claim 46 wherein the therapeutically effective amount is from about 10 to about 200 milliCuries of the radiolabeled composition.

49. A pharmaceutical composition comprising the composition of claim 43 and a pharmaceutically acceptable carrier.

50. A composition comprising a complex formed by reacting the reagent of claim 1 with a non-radioactive metal.

51. The composition of claim 50, wherein the non-radioactive metal is rhenium.

52. A composition comprising a complex formed by reacting the composition of claim 3 with a non-radioactive metal.

53. A composition comprising a complex formed by reacting the scintigraphic imaging agent of claim 5 with a non-radioactive metal.

54. A composition comprising a complex formed by reacting the scintigraphic imaging agent of claim 6 with a non-radioactive metal.

55. A composition comprising a complex formed by reacting the radiotherapeutic agent of claim 7 with a non-radioactive metal.

56. A method of imaging a site within a mammalian body comprising the steps of administering an effective diagnostic amount of the reagent of claim 1 radiolabeled with a detectable radioisotope and detecting the radioisotope localized at the site.
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