SSTR1-selective analogs

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-Trp 8 , IAmp 9 , Tyr 11 ]-SRIF and counterparts incorporating Cbm at the N-terminus, as well as radioiodinated versions thereof, 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.

1 . A cyclic somatostatin (SRIF) analog peptide which selectively binds the SRIF receptor SSTR1, which peptide has the amino acid sequence: (cyclo 3-14)H-Cys-Lys-Phe-Phe-D-Trp-IAmp-Thr-X-Thr-Ser-Cys-OH, where X is Tyr or ITyr.  
   
   
       2 . The peptide of  claim 1  wherein X is Tyr.  
   
   
       3 . The peptide of  claim 1  wherein X is ITyr and I is radioactive iodine.  
   
   
       4 . A method for detecting the presence of cells having SSTR1 by administering an effective amount of the peptide according to  claim 3  so as to selectively bind to such cells and provide a detectable signal at the location thereof.  
   
   
       5 . A method for screening for ligands that bind with high affinity to SSTR1, which method comprises carrying out a competitive binding assay with SSTR1, the peptide according to  claim 3  and a candidate ligand, and determining the ability of the said candidate ligand to displace said labeled peptide.  
   
   
       6 . A pharmaceutical composition comprising a mixture of the peptide according to  claim 1  and at least one pharmaceutically acceptable carrier.  
   
   
       7 . A method of treating IH or another SSTR1-mediated physiopathology, which method comprises administering an amount of the composition according to  claim 6 , which amount is effective to reach tissue affected thereby having SSTR1 receptors and activate said receptors.  
   
   
       8 . A cyclic somatostatin (SRIF) analog peptide which selectively binds the SRIF receptor SSTR1, which peptide has the amino acid sequence: (cyclo 3-14)X 1 -X 2 -Cys-Lys-Phe-Phe-D-Trp-IAmp-Thr-X 11 -Thr-Ser-Cys-OH wherein X 1  is H, 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; X 2  is Gly or des-X 2 ; and X 11  is Tyr, or ITyr.  
   
   
       9 . The peptide according to  claim 8  wherein X 1  is a conjugating/complexing agent capable of linking to a cytotoxin or completing to a radioactive nuclide.  
   
   
       10 . The peptide according to  claim 9  wherein X 1  is a polyaminopolycarboxylic conjugating agent.  
   
   
       11 . The peptide according to  claim 9  wherein said conjugating/complexing agent is DOTA, DTPA, HYNIC or P 2 S 2 —COOH.  
   
   
       12 . A pharmaceutical composition comprising a mixture of the peptide according to  claim 9  and at least one pharmaceutically acceptable carrier.  
   
   
       13 . A method for destroying SSTR1-containing cells, which method comprises administering thereto an amount of the peptide according to  claim 12  which includes a radioactive nuclide or a cytotoxin, which amount is effective to destroy such cells.