Radio-pharmaceutical complexes

Abstract

The invention provides a method for the formation of a tissue-targeting thorium complex, said method comprising; a) forming an octadentate chelator comprising four hydroxypyridinone (HOPO) moieties, substituted in the N-position with a methyl group, and a coupling moiety terminating in a carboxylic acid group; b) coupling said octadentate chelator to at least one tissue-targeting moiety targeting HER2; and c) contacting said tissue-targeting chelator with an aqueous solution comprising an ion of at least one alpha-emitting thorium isotope. A method of treatment of a neoplastic or hyperplastic disease comprising administration of such a tissue-targeting thorium complex, as well as the complex and corresponding pharmaceutical formulations are also provided

1 - 8 . (canceled) 
     
     
         9 . A tissue-targeting thorium complex formed or formable by the method comprising:
 a) forming an octadentate chelator of formula (I) or (II):   
       
         
           
           
               
               
           
         
         wherein R C  is a linker moiety terminating in a carboxylic acid moiety; 
         b) coupling said octadentate chelator to a tissue-targeting moiety comprising a light chain sequence which is SEQ ID No 1, 
         and a heavy chain with sequence similarity or identity of at least 80% with any one of the complete sequences of SEQ ED Nos 2-6, 
         thereby generating a tissue-targeting chelator; and 
         c) contacting said tissue-targeting chelator with an aqueous solution comprising 4 +  ions of the alpha emitting thorium isotope  227 Th, thereby generating the tissue-targeting thorium complex. 
       
     
     
         10 . A pharmaceutical formulation comprising at least one tissue-targeting thorium complex as defined in  claim 9 . 
     
     
         11 . The pharmaceutical formulation of  claim 10  further comprising citrate buffer. 
     
     
         12 . The pharmaceutical formulation of  claim 10  further comprising p-aminobutyric acid (PABA), and optionally EDTA and/or at least one polysorbate. 
     
     
         13 . A method of treatment of a hyperplastic or neoplastic disease in a human or non-human animal in need thereof comprising administration of at least one tissue-targeting thorium complex as defined in  claim 9 . 
     
     
         14 . The method of  claim 13 , wherein said disease is selected from the group consisting of gastric cancers, ovarian cancers, non-small-cell lung carcinomas (NSCLC), and uterine cancers. 
     
     
         15 . A method of treatment of a hyperplastic or neoplastic disease in a human or non-human animal in need thereof comprising administration of at least one tissue-targeting thorium complex as defined in  claim 9 . 
     
     
         16 . The method of  claim 15 , wherein the disease is selected from the group consisting of gastric cancers, ovarian cancers, non-small-cell lung carcinomas (NSCLC), and uterine cancers. 
     
     
         17 . (canceled) 
     
     
         18 . A kit comprising:
 i) an octadentate chelator as defined in  claim 9 ;   ii) at least one tissue-targeting moiety as defined in  claim 9 ;   iii) at least one amide-coupling reagent; and   iv) optionally an alpha-emitting thorium radionuclide, such as  227 Th.   
     
     
         19 . The tissue-targeting thorium complex of  claim 9 , wherein R C  is selected from the group consisting of:
 [—CH 2 -Ph-N(H)—C(═O)—CH 2 —CH 2 —C(═O)OH],   [—CH 2 —CH 2 —N(H)—C(═O)—(CH 2 —CH 2 —O) 1-3 —CH 2 —CH 2 —C(═O)OH], and   [—(CH 2 ) 1-3 -Ph-N(H)—C(═O)—(CH 2 ) 1-5 —C(═O)OH], wherein Ph is a phenylene group.   
     
     
         20 . The tissue-targeting thorium complex of  claim 19 , wherein Ph is a para-phenylene group. 
     
     
         21 . The tissue-targeting thorium complex of  claim 9 , wherein step b) is conducted in aqueous solution. 
     
     
         22 . The tissue-targeting thorium complex of  claim 9 , wherein the amide-coupling reagent is a carbodiimide coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N′-diisopropylcarbodiimide (DIC) or N,N′-dicyclohexylcarbodiimide (DCC). 
     
     
         23 . The tissue-targeting thorium complex of  claim 9 , wherein step b) is conducted in aqueous solution at pH between 4 and 9. 
     
     
         24 . The tissue-targeting thorium complex of  claim 9 , wherein step b) is conducted between 15 and 50° C. for 5 to 120 minutes. 
     
     
         25 . The tissue-targeting thorium complex of  claim 9 , wherein step c) is conducted between 15 and 50° C. for 1 to 60 minutes. 
     
     
         26 . The tissue-targeting thorium complex of  claim 9 , wherein R C  is [—(CH 2 ) 1-3 -para-phenylene-N(H)—C(═O)—(CH 2 ) 1-5 —C(═O)OH]. 
     
     
         27 . The tissue-targeting thorium complex of  claim 9 , wherein R C  is [—(CH 2 )-para-phenylene-N(H)—C(═O)—(CH 2 ) 2 —C(═O)OH]. 
     
     
         28 . The tissue-targeting thorium complex of  claim 9 , wherein the complex comprises a light chain of SEQ ID No 1 and a heavy chain with sequence similarity of 98% or more or identity with SEQ ID No 2.