SSTR1-selective analogs

• US 7,019,109 B2
• Filed: 03/15/2002
• Issued: 03/28/2006
• Est. Priority Date: 03/16/2001
• Status: Expired due to Fees

• Current Assignee: The SALK Institute For Biological Studies
• Original Assignee: Salk Institute for Biological Studies
• Inventors: Reubi, Jean Claude, Rivier, Jean E. F.
• Primary Examiner(s): Tate, Christopher R.
• Assistant Examiner(s): Kosar, Andrew D.
• Application Number:
  US10/099,240
• Publication Number:
  US 20020173618A1
• Time in Patent Office: 1,474 Days
• Field of Search: 530/300, 530/311, 530/317, 514/2
• US Class Current: 530/311
• 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: C07K 14/6555 at least 1 amino acid in D-form

Abstract

Analogs of SRIF which are selective for SSTR1 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR1 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA^1,2,5[D-Trp⁸, N^αMeIAmp⁹, Tyr¹¹]-SRIF and counterparts incorporating Cbm at the N-terminus and/or N^αSer¹³, inhibit the binding of a universal SRIF radioligand to the cloned human receptor SSTR1, but they do not bind with significant affinity to human SSTR2, SSTR3, SSTR4 or SSTR5. By incorporating an iodinated tyrosine in position-2 or in position-11 in these SSTR1-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. The N-terminus accommodates bulky moieties without loss of selectivity, and a carbamoyl moiety or a conjugating agent that will accept a radioactive nuclide or will link to a cytotoxin may be present at the N-terminus.

Claims

1. A cyclic somatostatin (SRIF) analog peptide which selectively binds SRIF receptor SSTR1, which peptide has the amino acid sequence (cyclo 3-14) X₁-X₂-X₃-Lys-Phe-X₇-X₈-X₉-Thr-X₁₁-Thr-X₁₃-Cys wherein:

X₁ is des-X₁, Ala, D-Ala, Cbm, Biu, (lower alkyl)Cbm, L-Hor, an acyl group having up to 20 carbon atoms, lower alkyl or a conjugating/complexing agent;

X₂ is Tyr, ITyr, D-Tyr, D-ITyr, Gly, or des-X₂;

X₃ is Cys or D-Cys;

X₇ is (A)Phe wherein A is H, Cl, F, Br, NO₂, Me, or NH(Q), where Q is H, Cbm, or L-Hor;

X₈ is a D-isomer amino acid having an aromatic side chain;

X₉ is an aminomethyl Phe wherein the side chain is (C₂ to C₅)alkylated and which is N^α

methylated;

X₁₁ is Phe, Tyr or ITyr; and

X₁₃ is Ser, N^α

MeSer or D-Ser.

2. The peptide according to claim 1 wherein:

X₁ is des-X₁, D-Ala, Ala, Cbm, Biu, L-Hor or an acyl group having up to 7 carbon atoms;

X₂ is Tyr, ITyr, D-Tyr, D-ITyr or des-X₂;

X₃ is Cys or D-Cys;

X₇ is (A)Phe wherein A is H, 4Cl, 4F or NO₂;

X₈ is a D-isomer amino acid having an aromatic side chain; and

X₉ is IAmp.

3. The peptide according to claim 2 wherein X₈ is D-Trp.

4. The peptide according to claim 2 wherein X₈ is D-2Nal.

5. The peptide according to claim 2 wherein X₁ is des-X₁, X₂ is des-X₂ and X₁₁ is Tyr or ITyr.

6. The peptide according to claim 1 wherein X₁ is a conjugating/complexing agent capable of linking to a cytotoxin or complexing to a radioactive nuclide.

7. The peptide according to claim 6 wherein X₈ is D-Trp or D-2Nal and X₁₁ is Tyr.

8. The peptide according to claim 6 wherein X₁ is a polyaminopolycarboxylic conjugating agent.

9. The peptide of according to claim 6 wherein said conjugating/complexing agent is DOTA, DTPA, HYNIC or P₂S₂-COOH.

10. The peptide according to claim 1 having the amino acid sequence:

(cyclo 3-14) X₁-X₂-X₃-Lys-Phe-X₇-X₈-N^α

MeIAmp-Thr-X₁₁-Thr-X₁₃-Cys wherein;

X₁ is Cbm;

X₂ is des-X₂;

X₈ is D-Trp or D-2Nal; and

X₁₁ is Tyr or ITyr.

11. The peptide according to claim 1 having the amino acid sequence:

(cyclo 3-14) X₁-Cys-Lys-Phe-X₇-X₈-N^α

MeIAmp-Thr-X₁₁-Thr-X₁₃-Cys wherein;

X₁ is Cbm or des-X₁;

X₇ is Phe or 4NO₂Phe; and

X₁₁ is Tyr or ITyr.

12. A pharmaceutical composition comprising a mixture of the peptide according to claim 1 and at least one phamaceutically acceptable carrier.

20. The peptide according to claim 1 having the amino acid sequence:

(cyclo 3-14) X₁-Cys-Lys-Phe-X₇-D-Trp -N^α

MeIAmp-Thr-X₁₁-Thr-X₁₃-Cys wherein;

X₁ is Cbm or des-X₁;

X₇ is Phe or 4NO₂Phe;

X₁₁ is Tyr or ITyr; and

X₁₃ is Ser or N^α

MeSer.

13. A cyclic somatostatin (SRIF) analog peptide having the amino acid sequence:

(cyclo 3-14) X₁-X₂-X₃-Lys-Phe -Phe-D-Trp-N^α

MeIAmp-Thr-X₁₁-Thr-Ser-Cys wherein;

X₁ is Cbm or des-X₁;

X₂ is Tyr, ITyr, D-Tyr, D-ITyr or des-X₂;

X₃ is Cys or D-Cys; and

X₁₁ is Phe, Tyr or ITyr.

14. The peptide of claim 13, wherein X₁₁ is Tyr or ITyr and I is radioactive.

15. The peptige according to claim 13 having the amino acid sequence:

(cyclo 3-14)H-Cys-Lys-Phe-Phe-D-Trp-N^α

MeIAmp-Thr-Tyr-Thr-Ser-Cys-OH.

16. A cyclic somatostatin (SRIF) analog peptide which selectively binds the SRIF receptor SSTR1, which peptide has the amino acid sequence (cyclo 3-14) X₁-X₂-X₃-Lys-Phe-Phe-D-Trp-X₉-Thr-X₁₁-Thr-Ser-Cys wherein:

X₁ is des-X₁, Ala, D-Ala, Cbm, Biu, (lower alkyl)Cbm, L-Hor, an acyl group having up to 20 carbon atoms, lower alkyl or a conjugating/complexing agent;

X₂ is Tyr, ITyr, D-Tyr, D-ITyr, Gly, or des-X₂;

X₃ is Cys or D-Cys;

X₉ is an aminomethyl Phe which is N^α

methyated and has a side chain that is (C₂ to C₅)alkylated;

X₁₁ is Phe, Tyr, D-Tyr, ITyr or D-ITyr; and

X₁₃ is Ser, N^α

MeSer or D-Ser.

17. The peptide according to claim 16 wherein:

X₁ is Cbm, Biu, (lower alkyl)Cbm or des-X₁;

X₂ is des-X₂; and

X₁₁ is Tyr or ITyr.

18. The peptide according to claim 16 wherein X₁ is Cbm and X₉ is N^α

MeIAmp.

19. The peptide according to claim 16 wherein X₁₃ is is N^α

MeSer.