Radiolabeled GRPR-Antagonists For Diagnostic Imaging and Treatment of GRPR-Positive Cancer

Abstract

The present invention relates to probes for use in the detection, imaging, diagnosis, targeting, treatment, etc. of cancers expressing the gastrin releasing peptide receptor (GRPR). For example, such probes may be molecules conjugated to detectable labels which are preferably moieties suitable for detection by gamma imaging and SPECT or by positron emission tomography (PET) or magnetic resonance imaging (MRI) or fluorescence spectroscopy or optical imaging methods.

1 . A GRPR-antagonist of the general formula:
   MC—S—P
   wherein:
 at least one (radio)metal (M) and a chelator (C) which stably binds M; alternatively MC may represent a Tyr- or a prosthetic group carrying a (radio)halogen; 
   S is an optional spacer covalently linked between the N-terminal of P and C and may be selected to provide a means for (radio)halogenation;   P is a GRP receptor peptide antagonist of the general formula:
   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -CO—Z
 
   Xaa 1  is not present or is selected from the group consisting of amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), ß-naphthylalanine (ß-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (o-I-Tyr), Trp, pentafluorophenylalanine (5-F-Phe) (all as L- or D-isomers);
 Xaa 2  is Gln, Asn, His 
 Xaa 3  is Trp, 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi) 
 Xaa 4  is Ala, Ser, Val 
 Xaa 5  is Val, Ser, Thr 
 Xaa 6  is Gly, sarcosine (Sar), D-Ala, ß-Ala 
 Xaa 7  is His, (3-methyl)histidine (3-Me)His 
 Z is selected from —NHOH, —NHNH 2 , —NH-alkyl, —N(alkyl) 2 , or —O-alkyl or 
   
       
         
           
           
               
               
           
         
         
           
             wherein X is NH (amide) or O (ester) and R1 and R2 are the same or different and selected from a proton, a (substituted)alkyl, a (substituted) alkyl ether, an aryl, an aryl ether or an alkyl-, halogen, hydroxyl or hydroxyalkyl substituted aromatic group. 
           
         
       
     
     
         2 . The GRPR-antagonist as claimed in  claim 1 , wherein
 Z is preferably selected from one of the following formulae, wherein X is NH or O:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The GRPR-antagonist as claimed in  claim 2 , wherein R1 is the same as R2. 
     
     
         4 . The GRPR-antagonist of  claim 1 , wherein P is selected from the group consisting of:
 DPhe-Gln-Trp-Ala-Val-Gly-His-CO—NH—CH[CH 2 —CH(CH 3 ) 2 ] 2  (SEQ ID NO: 1);   DPhe-Gln-Trp-Ala-Val-Gly-His-CO—O—CH[CH 2 —CH(CH 3 ) 2 ] 2  (SEQ ID NO:2);   DPhe-Gln-Trp-Ala-Val-Gly-His-CO—NH—CH(CH 2 —CH 2 —CH 2 —CH 3 ) 2  (SEQ ID NO:3);   DTyr-Gln-Trp-Ala-Val-Gly-His-CO—NH—CH[CH 2 —CH(CH 3 ) 2 ] 2  (SEQ ID NO: 4).   
     
     
         5 . The GRPR-antagonist of  claim 1 , wherein the radionuclide metal M or radiohalogen is suitable for diagnostic or therapeutic use, in particular for imaging or radionuclide therapy and selected from the group consisting of  111 In,  133m In,  99m Tc,  94m Tc,  67 Ga,  66 Ga,  68 Ga,  52 Fe,  69 Er,  72 As,  97 Ru,  23 Pb,  62 Cu,  64 Cu,  67 C,  186 Re,  188 Re,  86 Y,  90 Y,  51 Cr,  52m Mn,  157 Gd,  177 Lu,  161 Tb,  169 Yb,  175 Yb,  115 Rh,  166 Dy,  166 Ho,  153 Sm,  149 Pm,  151 Pm,  172 Tm,  121 Sn,  177m Sn,  213 Bi,  142 Pr,  143 Pr,  198 Au,  199 Au, halogens:  123 I,  124 I,  125 I,  18 F, a.o. 
     
     
         6 . The GRPR-antagonist of  claim 1 , wherein the metal chelator C is a metal chelator for di- and trivalent metals. 
     
     
         7 . The GRPR-antagonist as claimed in  claim 6 , wherein the metal chelator for di- and trivalent metals is a DTPA-, NOTA-, DOTA-, or TETA-based chelator or a mono- or bifunctional derivative thereof. 
     
     
         8 . The GRPR-antagonist as claimed in  claim 7 , wherein the metal chelator C is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The GRPR-antagonist of  claim 1 , wherein the metal chelator C is a metal chelator for technetium or rhenium. 
     
     
         10 . The GRPR-antagonist as claimed in  claim 9 , wherein C is selected from acyclic tetraamine-, cyclam-, PnAO-, or tetradentate chelators containing P 2 S 2 —, N 2 S 2 - and N 3 S-donor atom sets and mono- and bifunctional derivatives thereof, or HYNIC/co-ligand-based chelators, or bi- and tridentate chelators forming organometallic complexes via the tricarbonyl technology. 
     
     
         11 . The GRPR-antagonist as claimed in  claim 9 , wherein C is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The GRPR-antagonist of  claim 1 , wherein the spacer S is linked between P and C by covalent bonds and may be selected to provide a means for (radio)iodination. 
     
     
         13 . The GRPR-antagonist as claimed in  claim 12 , wherein S is selected from the group consisting of:
 a) aryl containing residues of the formulae:   
       
         
           
           
               
               
           
         
         wherein PABA is p-aminobenzoic acid, PABZA is p-aminobenzylamine, PDA is phenylenediamine and PAMBZA is p-(aminomethyl)benzylamine; 
         b) dicarboxylic acids, ω-aminocarboxylic acids, α,ω-diaminocarboxylic acids or diamines of the formulae: 
       
       
         
           
           
               
               
           
         
         wherein DIG is diglycolic acid and IDA is iminodiacetic acid; 
         c) PEG spacers of various chain lengths, in particular PEG spacers selected from the formulae: 
       
       
         
           
           
               
               
           
         
         c) α- and ß-amino acids, single or in homologous chains of various chain lengths or heterologous chains of various chain lengths, in particular: 
       
       
         
           
           
               
               
           
         
         GRP(1-18), GRP(14-18), GRP(13-18), BBN(1-5), or [Tyr 4 ]BBN(1-5); or 
         d) combinations of a, b and c. 
       
     
     
         14 . The GRPR-antagonist as claimed in  claim 13 , selected from the group consisting of compounds of the formulae: 
       
         
           
           
               
               
           
         
         wherein MC and P are as defined in any one of the preceding claims. 
       
     
     
         15 . (canceled) 
     
     
         16 . A method of diagnosing and/or treating primary and/or metastatic GRPR-positive cancer, the method comprising administering an effective amount of the radiolabeled GRPR-antagonist of  claim 1  to a subject. 
     
     
         17 . The method of  claim 16 , wherein the cancer is selected from prostate cancer, breast cancer, small cell lung cancer, colon carcinoma, gastrointestinal stromal tumors, gastrinoma, renal cell carcinomas, gastroenteropancreatic neuroendocrine tumors, oesophageal squamous cell tumors, neuroblastomas, head and neck squamous cell carcinomas, as well as in ovarian, endometrial and pancreatic tumors displaying neoplasia-related vasculature that is GRPR-positive. 
     
     
         18 . The method of  claim 16 , wherein the subject is human. 
     
     
         19 . A diagnostic and/or therapeutic composition, comprising the radiolabeled GRPR-antagonist as claimed in  claim 1  and a therapeutically acceptable excipient.