Somatostatin analogs

• US 6,358,491 B1
• Filed: 09/16/1999
• Issued: 03/19/2002
• Est. Priority Date: 08/27/1999
• Status: Expired due to Term

• Current Assignee: Bryan Oncor, Inc.
• Original Assignee: Berlex Laboratories Incorporated (Bayer AG)
• Inventors: Wilson, David M., Lister-James, John, Pearson, Daniel A., Dean, Richard T.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/397,792
• Time in Patent Office: 915 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.69, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 530/300, 530/311, 530/317, 530/324-330, 534/7, 534/10-16, 206/223, 206/569, 206/570
• US Class Current: 424/1.69
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 51/08 Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins
• CPC Class Codes: A61K 51/083 the peptide being octreotide or a somatostatin-receptor-binding peptide
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form

Abstract

The invention provides novel peptide-based pharmacophores and compounds which bind somatostatin receptors with high affinity and which exhibit improved pharmacokinetic properties over known somatostatin analogs. The pharmacophores and compounds of the invention may be used in labeled or unlabeled form for diagnosing and/or treating somatostatin responsive diseases. The invention also provides radiopharmaceuticals and kits comprising these compounds, as well as methods for diagnosing and/or treating somatostatin receptor mediated diseases.

Claims

1. A compound comprising a somatostatin receptor-binding peptide having a formula

2. The compound of claim 1, wherein A is an N-methyl-α

-amino acid.

3. The compound of claim 2, wherein A is selected from the group consisting of (N—

CH₃)Cys, (N—

CH₃)Hcy, (N—

CH₃)Tyr, (N—

CH₃)Tyr, and (N—

CH₃)Tyr(CH₂CH₂SH).

4. The compound of claim 3, wherein A is selected from the group consisting of (N—

CH₃)Cys, (N—

CH₃)Hcy, and (N—

CH₃)Tyr, and C is selected from the group consisting of L-methionine, L-phenylalanine, and a substituted derivative of L-phenylalanine.

5. The compound of claim 4, wherein A is selected from the group consisting of (N—

CH₃)Cys and (N—

CH₃)Hcy, and C is selected from the group consisting of L -methionine, L-phenylalanine, and a substituted derivative of L-phenylalanine.

6. The compound of claim 5, wherein A is (N—

CH₃)Hcy and C is L-phenylalanine.

7. The compound of claim 1, having the formula:

8. The compound of claim 1, wherein a chelator or radiometal ligand is covalently linked to a sidechain of A.

9. The compound of claim 8, wherein the chelator has a formula:

10. The compound of claim 8, wherein the chelator is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, a substituted derivative of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, and a substituted derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

11. The compound of claim 8, wherein the ligand is a hydrazino nicotinamide moiety.

17. A radiopharmaceutical comprising the compound of any of claims 1 through 16 and a radioisotope selected from the group consisting of an α

-emitting radionuclide, a β

-emitting radionuclide, a β

-/γ

-emitting radionuclide, a positron emitting radionuclide, and a γ

-emitting radionuclide.

18. The radiopharmaceutical of claim 17, wherein the radioisotope is selected from the group consisting of ⁶⁸Ga, ⁶⁷Ga, ⁶⁷Cu, ⁴⁷Sc, ¹¹¹In, ^99mTc, ¹⁸⁶Re, ¹⁸⁸Re, ²¹²Bi, ²¹³Bi, ⁹⁰Y, ⁶⁴Cu, ¹⁵³Sm, ^94mTc, ¹⁶⁶Ho, ²²³Ra, ²²⁵Ac.

19. The radiopharmaceutical of claim 17, wherein the radioisotope is selected from the group consisting of ¹⁸F, ¹²⁵I, ¹³¹I, ¹²³I, and ²¹¹At.

27. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the compound of any of claims 1 through 16 and an effective amount of a reducing agent to label the compound with ^99mTc, ¹⁸⁶Re or ¹⁸⁸Re.

30. A kit comprising a sealed vial containing a predetermined quantity of the compound of any of claims 1 through 16.

33. A method of imaging a site within a mammalian body comprising the steps of:

a) radiolabeling the compound of any of claims 1 through 16 with ^99mTc;

b) administering an effective diagnostic amount of the radiolabeled compound to the body; and

c) detecting ^99mTc accumulated at the site.

36. A method of treating an animal suffering a somatostatin-responsive disease, comprising the steps of:

a) radiolabeling the compound of any of claims 1 through 16 with ¹⁸⁶Re, ¹⁸⁸Re, ²¹²Bi, ²¹³Bi, ⁹⁰Y, ¹⁵³Sm, ⁴⁷Sc, ⁶⁸Ga, ^94mTc, ⁶⁷Cu, 166Ho, ²²³Ra, ²²⁵Ac, ¹⁸F, ¹²⁵I, ¹³¹I, ¹²³I, or ²¹¹At; and

b) administering a therapeutically effective amount of the radiolabeled compound to the animal.

40. A method of treating an animal suffering a somatostatin-responsive disease, comprising the step of administering a therapeutically effective amount of the compound of any of claims 1 through 16 to the animal.

43. A method of treating a tumor in a mammal comprising the steps of:

a) combining a first aliquot of the compound of any of claims 1 through 16 with ^99mTc to form a diagnostic agent;

b) administering an effective diagnostic amount of the diagnostic agent to the mammal;

c) detecting ^99mTc accumulated in the mammal, thereby determining the presence of a SSTR-expressing tumor;

d) combining a second aliquot of said compound with a cytotoxic radioisotope to form a radiotherapeutic agent; and

e) administering a therapeutically effective amount of the radiotherapeutic agent to the mammal.

12. A compound having a formula

13. The compound of claim 12, wherein X is a chelator having a formula:

14. The compound of claim 13, wherein Xaa is selected from the group consisting of serine, diaminobutyric acid, histidine, arginine, tyrosine, iodotyrosine, bromotyrosine, chlorotyrosine, O-alkyl-tyrosine where alkyl represents C₁ to C₄ alkyl, hydroxyltyrosine, aminotyrosine, phenylalanine, 4-fluorophenylalanine, 4-chlorophenylalanine, 4-bromophenylalanine, 4-iodophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, N⁴—

R-4-aminophenylalanine, N⁴—

R, N⁴—

R′

-4-aminophenylalanine, or 3-R′

-4-aminophenylalanine where R is C₁ to C₄ alkyl and R′

is selected from the group consisting of H, C₁ to C₄ alkyl, amino, hydroxyl, NH-alkyl wherein alkyl represents C₁ to C₄ alkyl, NH-acyl, O-alkyl wherein alkyl represents C₁ to C₄ alkyl, O-acyl, S-alkyl wherein alkyl represents C₁ to C₄ alkyl, SO-alkyl and SO₂-alkyl wherein alkyl represents C₁ to C₄ alkyl, SO₃H, CO₂H, CO₂-alkyl wherein alkyl represents C₁ to C₄ alkyl, and CONH-alkyl wherein alkyl represents C₁ to C₄ alkyl.

15. The compound of claim 12, wherein X is a hydrazino nicotinamide moiety.

16. The compound of claim 12, wherein X is a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, a substituted derivative of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, or a substituted derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

20. A compound having a formula selected from the group consisting of:

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Tyr-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Phe(₄-F)-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Phe(₄NH₂)-Cys-Thr-Ser);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Dab-Cys-Thr);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Phe(₄-NH₂)-Cys-Thr);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Phe(₄-NH₂)-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Gly-Gly-Cys-Lys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-His-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Arg-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Gly-Cys-Lys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Ser-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Dab-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Gly-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Dab-Cys-Ser(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Gly-Gly-Cys-Lys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Gly-Gly-Cys-Arg-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Ser-Cys-Lys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Ser-Cys-Arg-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Ser-Cys-Lys-Thr-(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Ser-Cys-Dap-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Ser-Cys-NH(CH_{2 CH2 O})_{2 CH2 CH2 NH2});

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Ser-Cys-Thr-NH(CH_{2 O})_{2 CH2 CH2 NH2});

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Gly-Lys-Cys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Lys-Cys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Lys-Gly-Cys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Dab-Cys-Ser-(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Dab-Cys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Gly-Gly-Cys-His-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Gly-Gly-Cys-Phe-(4-NH₂)—

NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Orn-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Dap-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Lys-Cys-Thr(ol));

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Ser-Ser-Cys-NHCH_{2 CH2 OCH2 CH2 NH2});

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-β

-Dap-Lys-Cys-NH₂);

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-δ

-Orn-Gly-Cys-NH₂); and

cyclo-Tyr-D-Trp-Lys-Thr-Phe-(N—

CH₃)Hcy(CH₂CO-Thr-Gly-Gly-Cys-NH₂).

21. A radiopharmaceutical comprising the compound of claim 20 and a radioisotope selected from the group consisting of ^99mTc, ¹⁸⁶Re, ¹⁸⁸Re, ²¹²Bi, and ²¹³Bi.

28. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the compound of claim 20 and an effective amount of a reducing agent to label the compound with ^99mTc, ¹⁸⁶Re or ¹⁸⁸Re.

31. A kit comprising a sealed vial containing a predetermined quantity of the compound of claim 20.

34. A method of imaging a site within a mammalian body comprising the steps of:

a) radiolabeling the compound of claim 20 with ^99mTc;

b) administering an effective diagnostic amount of the radiolabeled compound to the body; and

c) detecting ^99mTc accumulated at the site.

37. A method of treating an animal suffering a somatostatin-responsive disease, comprising the steps of:

a) radiolabeling the compound of claim 20 with ¹⁸⁶Re, ¹⁸⁸Re, ²¹²Bi, or ²¹³Bi; and

b) administering a therapeutically effective amount of the radiolabeled compound to the animal.

38. A method of treating an animal suffering a disease wherein somatostatin receptors are up-regulated, comprising the steps of:

a) radiolabeling the compound of claim 20 with ¹⁸⁶Re, ¹⁸⁸Re, ²¹²Bi, or ²¹³Bi; and

b) administering an effective therapeutic amount of the radiolabeled compound to the animal.

41. A method of treating an animal suffering a somatostatin-responsive disease, comprising the step of administering an effective therapeutic amount of the compound of claim 20 to the animal.

44. A method of treating a tumor in a mammal comprising the steps of:

a) combining a first aliquot of the compound of claim 20 with ^99mTc to form a diagnostic agent;

b) administering an effective diagnostic amount of the diagnostic agent to the mammal;

c) detecting ^99mTc accumulated in the mammal, thereby determining the presence of a SSTR-expressing tumor;

d) combining a second aliquot of said compound with a cytotoxic radioisotope to form a radiotherapeutic agent; and

e) administering a therapeutically effective amount of the radiotherapeutic agent to the mammal.

22. A compound having a formula:

23. A radiopharmaceutical comprising the compound of claim 22 and ^99mTc.

24. A radiopharmaceutical comprising the compound of claim 22 and ¹⁸⁸Re.

29. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of the compound of claim 22 and an effective amount of a reducing agent to label the compound with ^99mTc, ¹⁸⁶Re or ¹⁸⁸Re.

32. A kit comprising a sealed vial containing a predetermined quantity of the compound of claim 22.

35. A method of imaging a site within a mammalian body comprising the steps of:

a) administering an effective diagnostic amount of the radiopharmaceutical of claim 23 to the body; and

c) detecting ^99mTc accumulated at the site.

39. A method of treating an animal suffering a somatostatin-responsive disease, comprising the step of:

administering a therapeutically effective amount of the radiopharmaceutical of claim 24 to the animal.

42. A method of treating an animal suffering a somatostatin-responsive disease, comprising the step of administering an effective therapeutic amount of the compound of claim 22 to the animal.

25. A complex of ^99mTc and a compound having a formula:

26. A complex of ¹⁸⁶Re or ¹⁸⁸Re and a compound having a formula:

45. A method of treating a tumor in a mammal comprising the steps of:

a) combining a first aliquot of a compound having a formula;