Bombesin analog peptide antagonist conjugates

Abstract

To provide a diagnostic and therapeutic medicament, a bombesin analog peptide antagonist conjugate is provided which has general Formula (I), wherein A is a metal chelator comprising at least one radionuclide metal, B is a spacer linked to N-terminal of C or a covalent bond and C is a bombesin analog peptide antagonist having a sequence as claimed, where further x is an Integer from 1 to 3 and n is an integer from 1 to 6. [ A− ( B ) n ] x −C

1 - 19 . (canceled) 
     
     
         20 . A bombesin analog peptide antagonist conjugate having formula (I)
   A-B-C   (I)
   wherein   
       A is a metal chelator which is:
 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 
 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) or 
 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA) 
 and A contains a radionuclide metal conjugated thereto selected from the group consisting of 
 a)  68 Ga, and 
 b)  111 In, 
 
       B is a spacer linked to the N-terminal of C selected from the group consisting of:
 a) Gly-aminobenzoyl, 
 b) 4-amino-1-carboxymethyl-piperidine, 
 c) 4-amino-1-piperidine-4-carboxylic acid, 
 d) 15-amino-4,7,10,13-tetraoxapentadecanoic acid, 
 e) (15-amino-4,7,10,13-tetraoxapentadecanoic acid)-(4-amino-1-carboxy-methyl-piperidine), and 
 f) diaminobutyric acid, 
 
       and 
       C is a bombesin analog peptide antagonist of the following sequence
 D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 . 
 
     
     
         21 . A bombesin analog peptide antagonist conjugate of Formula (I′)
   A′-B-C   (I′)
 
 wherein 
 
       A′ is a metal chelator which is:
 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 
 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) or 
 1,4,7- triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), and is free of a radionuclide metal, 
 
       B is a spacer linked to the N-terminal of C selected from the group consisting of:
 a) Gly-aminobenzoyl, 
 b) 4-amino-1-carboxymethyl-piperidine, 
 c) 4-amino-1-piperidine-4-carboxylic acid, 
 d) 15-amino-4,7,10,13-tetraoxapentadecanoic acid, 
 e) (15-amino-4,7,10,13-tetraoxapentadecanoic acid)-(4-amino-1-carboxy-methyl-piperidine), and 
 f) diaminobutyric acid, 
 
       and 
       C is a bombesin analog peptide antagonist of the following sequence:
 D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 . 
 
     
     
         22 . A pharmaceutical composition comprising any one of the bombesin analog peptide antagonist conjugates according to  claim 20 . 
     
     
         23 . A method comprising binding any one of the bombesin analog peptide antagonist conjugates according to  claim 20  to a bombesin receptor. 
     
     
         24 . A method for preparing any one of the bombesin analog peptide antagonist conjugates according to  claim 20 , comprising:
 radiochelating a bombesin analog peptide antagonist conjugate having Formula (I′)
   A′-B-C (I′)
 
   
       wherein 
       A′ is included instead of A and has the same meaning as A except that it is a metal chelator free of radionuclide metal, 
       with a radionuclide metal selected from the group consisting of: 68Ga and  111 In. 
     
     
         25 . A method for imaging bombesin receptors in a patient, comprising:
 administering to a patient an imaging effective amount of a bombesin analog peptide antagonist conjugate according to  claim 20 ; and   imaging the radionuclide metal in the patient.   
     
     
         26 . A method according to  claim 25 , wherein the bombesin receptor imaged is a GRP receptor expressing tumor cells, tumoral vessels or peritumoral vessels. 
     
     
         27 . A method according to  claim 26 , wherein said tumor cells refer to tumor cells from cancers that are selected from the group consisting of:
 prostate cancer, including metastases,   breast cancer, including metastases,   gastrointestinal stromal tumors,   small cell lung carcinomas,   renal cell carcinomas,   gastroenteropancreatic neuroendocrine tumors,   head and neck squamous cell cancers,   neuroblastomas, and   oesophageal squamous cell carcinomas,   
       and wherein 
       said tumoral and peritumoral vessels refer to tumoral and peritumoral vessels from cancers that are selected from the group consisting of:
 ovarian cancers, 
 endometrial cancers, and 
 pancreatic cancers. 
 
     
     
         28 . A kit for the preparation of a radiopharmaceutical imaging agent comprising a vial containing a predetermined quantity of the bombesin analog peptide antagonist conjugate according to  claim 21  and an acceptable carrier, diluent, excipient or adjuvant for radiolabeling the agent. 
     
     
         29 . A method according to  claim 23 , wherein the bombesin receptor is a gastrin releasing peptide receptor (GRP). 
     
     
         30 . The bombesin analog peptide antagonist conjugate according to  claim 20 , wherein the radionuclide metal for imaging is  68 Ga. 
     
     
         31 . The bombesin analog peptide antagonist conjugate according to  claim 20 , wherein A is
 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA),   1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) or   1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA),   the radionuclide metal for imaging is  68 Ga and the spacer B is 4-amino-1-carboxymethyl-piperidine,
 which are the compounds of the following structures: 
   
       
         
           
           
               
               
           
         
       
     
     
         32 . A bombesin analog peptide antagonist conjugate according to  claim 21 , wherein A′ is
 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 
 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) or 
 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 
 and the spacer B is 4-amino-1-carboxymethyl-piperidine,
 which are the compounds of the following structures: