Radioactive transition metal nitride heterocomplex

Abstract

The present invention provides a single radioactive transition metal nitride heterocomplex which permits labeling of a physiologically active substance such as a peptide, hormone or the like without impairing the activity of the substance. The radioactive transition metal nitride heterocomplex of the present invention is represented by the following formula (I): (M═N)XY  (I) wherein a radioactive transition metal M is radioactive technetium or radioactive rhenium, N is a nitrogen atom, X is a diphosphine compound or a diarsine compound, and Y is a bindentate ligand having a combination of electron-donating atoms.

1 . A radioactive transition metal nitride heterocomplex comprising a radioactive transition metal nitride and two different ligands coordinated therewith which is represented by the following formula (I): 
       (M≡N)XY  (I) 
       wherein a radioactive transition metal M is a radioactive technetium or radioactive rhenium, N is a nitrogen atom, X is a diphosphine compound or a diarsine compound, and Y is a bidentate ligand having a combination of two electron-donating atoms which are selected from the group consisting of O, S and N and may be either charged or not.  
     
     
         2 . A radioactive transition metal nitride heterocomplex according to  claim 1 , wherein said diphosphine compound X is a bisphosphine compound represented by the following formula (II):  
       
         
           
           
               
               
           
         
       
       wherein each of R 1 , R 2 , R 3  and R 4 , which may be the same or different, is one member selected from the group consisting of a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group and a substituted aryl group, R 5  is a methylene group, Z is one member selected from the group consisting of an oxygen atom, a sulfur atom, a methylene group, NR 6  (wherein N is a nitrogen atom and R 6  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain, a biologically active group or a —C(═O)R 7  group (wherein R 7  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain or a biologically active group)) and an ethylenedioxy group, P is a phosphorus atom, n is an integer in a range of 1≦n≦5, and m is zero or 1.  
     
     
         3 . A radioactive transition metal nitride heterocomplex according to  claim 1  or  2 , wherein said diphosphine compound X is a bisphosphine compound represented by the following formula (III) or formula (IV):  
       
         
           
           
               
               
           
         
       
       (wherein Ph is a phenyl group and R 6  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain, a biologically active group or a —C(═O)R 7  group (wherein R 7  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain or a biologically active group)),  
       
         
           
           
               
               
           
         
       
       (wherein X is an integer in a range of 0≦X≦4, W is an integer in a range of 0≦W≦3, and R 6  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain, a biologically acitive group or a —C(═O)R 7  group (wherein R 7  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain or a biologically active group)).  
     
     
         4 . A radioactive transition metal nitride heterocomplex according to any one of  claims 1  to  3 , wherein said diphosphine compound is selected from the group consisting of bis(diphenylphosphinoethyl)amine, bis(diphenylphosphinoethyl)methylamine, bis(diphenylphosphinoethyl)ethylamine, bis(diphenylphosphinoethyl)propylamine, bis(diphenylphosphinoethyl)butylamine, bis(diphenylphosphinoethyl)acetonylamine and bis(diphenylphosphinoethyl)methoxy ethylamine.  
     
     
         5 . A radioactive transition metal nitride heterocomplex according to any one of  claims 1  to  3 , wherein said diphosphine compound is selected from the group consisting of (CH 3 O) 2 —P—CH 2 CH 2 —NH—CH 2 CH 2 —P—(OCH 3 ) 2 , (CH 3 O) 2 —P—CH 2 CH 2 —N(CH 3 )—CH 2 CH 2 —P—(OCH 3 ) 2 , (CH 3 O) 2 —P—CH 2 —N( CH 2 CH 3 )—CH 2 CH 2 —P—(OCH 3 ) 2 , (CH 3 O) 2 —P—CH 2 CH 2 —N(CH 2 CH 2 CH 3 )—CH 2 CH 2 —P—(OCH 3 ) 2 , [CH 3 O(CH 2 ) 3 ] 2 —P—CH 2 CH 2 —N(CH 2 CH 3 )—CH 2 CH 2 —P—[(CH 2 ) 3 OCH 3 ] 2 , [CH 3 O(CH 2 ) 3 ] 2 —P—CH 2 CH 2 —N(CH 2 CH 2 CH 3 )—CH 2 CH 2 —P—[(CH 2 ) 3 OCH 3 ] 2 , (CH 3 CH 2 OCH 2 CH 2 ) 2 —P—CH 2 CH 2 —N(CH 2 CH 3 )—CH 2 CH 2 —P—(CH 2 CH 2 OCH 2 CH 3 ) 2 , (CH 3 CH 2 OCH 2 CH 2 ) 2 —P—CH 2 CH 2 —N(CH 2 CH 2 CH 3 )—CH 2 CH 2 —P—(CH 2 CH 2 OCH 2 CH 3 ) 2 , [CH 3 O(CH 2 ) 3 ] 2 —P—CH 2 CH 2 —N(CH 2 CH 2 OCH 3 )—CH 2 CH 2 —P—[(CH 2 ) 3 OCH 3 ] 2 and (CH 3 CH 2 OCH 2 CH 2 ) 2 ——P—CH 2 CH 2 —N(CH 2 CH 2 OCH 3 )—CH 2 CH 2 —P—(CH 2 CH 2 OCH 2 CH 3 ) 2 .  
     
     
         6 . A radioactive transition metal nitride heterocomplex according to  claim 1  or  2 , wherein said diphosphine compound is selected from the group consisting of bis(diphenylphosphinoethyl)dioxyethylene, bis(dimethoxyphosphinoethyl)dioxyethylene, bis(diphenylphosphinoethyl)ether, bis(diphenylphosphinoethyl)sulfide and bis(diphenylphosphinoethyl)alkylene.  
     
     
         7 . A radioactive transition metal nitride heterocomplex according to any one of  claims 1  to  6 , wherein said bidentate ligand Y is a bidentate ligand having a combination of electron-donating atoms selected from the group consisting of [N − , S − ], [O − , S − ], [S − , S − ], [N − , S], [N, S − ], [O, S − ], [O, O − ], [O − , N − ], [N − , N − ], [O − , S], [O − , O − ], [O − , N], [S, S − ], [N, N − ], [O, N − ], [O, N], [N, N], [S, S], [O, O], [N, S] and [O, S].  
     
     
         8 . A radioactive transition metal nitride heterocomplex according to any one of  claims 1  to  7 , wherein said bidentate ligand Y is physiologically active.  
     
     
         9 . A radioactive transition metal nitride heterocomplex according to any one of  claims 1  to  8 , wherein said bidentate ligand Y comprises a combination of a physiologically active substance selected from the group consisting of a sugar, an amino acid, a fatty acid, a hormone, a peptide and a receptor-attachable ligand, and said electron-donating atoms.  
     
     
         10 . A radioactive transition metal nitride heterocomplex according to  claim 8  or  9 , wherein said bidentate ligand Y is one member selected from the group consisting of 1-thio-β-D-glucose, thiosalicylic acid, cysteine, cysteine ethyl ester, 2-aminoethanethiol, dithiocarbamic acid and derivatives thereof, and dithiocarbazic acid and derivatives thereof.  
     
     
         11 . A radioactive transition metal nitride heterocomplex according to  claim 10 , wherein said dithiocarbamic acid derivatives is one member selected from the group consisting of N-methyl-S-methyl dithiocarbamate, N-diethyl dithiocarbamate, N-ethyl dithiocarbamate and N-ethoxy-N-ethyl dithiocarbamate, or said dithiocarbazic acid derivatives is one member selected from the groups consisting of N-ethyl dithiocarbazate and N-methyl-S-methyl dithiocarbazate.  
     
     
         12 . A radioactive transition metal nitride heterocomplex according to any one of  claims 1  to  11 , wherein said radioactive transition metal M is one member selected from the group consisting of  99m Tc,  186 Re and  188 Re.  
     
     
         13 . A radiopharmaceutical containing a radioactive transition metal nitride heterocomplex according to any one of  claims 1  to  12  as an active ingredient.  
     
     
         14 . A process for producing a radioactive transition metal nitride heterocomplex according to  claim 1 , which comprises 
 a first step of reacting an oxide of a radioactive transition metal M with either carbazic acid or its derivative, or hydrazine or its derivative, and a diphosphine compound or a diarsine compound in a solution in the presence or absence of a reducing agent, to obtain an intermediate of radioactive transition metal nitride; and    a second step of reacting said intermediate with a bidentate ligand having a combination of two electron-donating atoms selected from the group consisting of O, S and N.    
     
     
         15 . A process according to  claim 14 , wherein said carbazic acid derivative is selected from the group consisting of N-methyl-S-methyl dithiocarbazate, S-methyl dithiocarbazate and N-methyl-S-2-propionic acid dithiocarbazate.  
     
     
         16 . A process according to  claim 14 , wherein said hydrazine derivative is selected from the group consisting of succinic acid hydrazide, acetyl hydrazide and isonicotinic acid hydrazide.  
     
     
         17 . A process according to any one of  claims 14  to  16 , wherein said diphosphine compound X is a bisphosphine compound represented by the following formula (II):  
       
         
           
           
               
               
           
         
       
       wherein each of R 1 , R 2 , R 3  and R 4 , which may be the same or different, is one member selected from the group consisting of a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group and a substituted aryl group, R 5  is a methylene group, Z is one member selected from the group consisting of an oxygen atom, a sulfur atom , a methylene group, NR 6  (wherein N is a nitrogen atom and R 6  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain, a biologically active group or a —C(═O)R 7  group (wherein R 7  is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, an amino acid chain or a biologically active group)) and an ethylenedioxy group, P is a phosphorus atom, n is an integer in a range of 1≦n≦5, and m is zero or 1.  
     
     
         18 . A process according to any one of  claims 14  to  17 , wherein said diphosphine compound is selected from the group consisting of bis(diphenylphosphinoethyl)amine, bis(diphenylphosphinoethyl)methylamine, bis(diphenylphosphinoethyl)ethylamine, bis(diphenylphosphinoethyl)propylamine, bis(diphenylphosphinoethyl)butylamine, bis(diphenylphosphinoethyl)acetonylamine and bis(diphenylphosphinoethyl)methoxyethylamine.  
     
     
         19 . A process according to any one of  claims 14  to  18 , wherein said diphosphine compound is selected from the group consisting of (CH 3 O) 2 —P—CH 2 CH 2 —NH—CH 2 CH 2 —P—(OCH 3 ) 2 , (CH 3 O) 2 —P—CH 2 CH 2 —N(CH 3 )—CH 2 CH 2 —P(OCH 3 ) 2 , (CH 3 O) 2 —P—CH 2 CH 2 —N(CH 2 CH 3 )—CH 2 CH 2 —P—(OCH 3 ) 2 , (CH 3 O) 2 —P—CH 2 CH 2 —N(CH 2 CH 2 CH 3 )—CH 2 CH 2 —P—(OCH 3 ) 2 , [CH 3 O(CH 2 ) 3 ] 2 —P—CH 2 CH 2 —N(CH 2 CH 3 )—CH 2 CH 2 —P—[(CH 2 ) 2 OCH 3 ] 2 , [CH 3 O(CH 2 ) 3 ] 2 —P—CH 2 CH 2 —N(CH 2 CH 2 CH 3 )—CH 2 CH 2 —P—[(CH 2 ) 3 OCH 3 ] 2 , (CH 3 CH 2 OCH 2 CH 2 ) 2 —P—CH 2 CH 2 —N(CH 2 CH 3 )—CH 2 CH 2 —P—(CH 2 CH 2 OCH 2 CH 3 ) 2 , (CH 3 CH 2 OCH 2 CH 2 ) 2 —P—CH 2 CH 2 —N(CH 2 CH 2 CH 3 )—CH 2 CH 2 —P—(CH 2 CH 2 OCH 2 CH 3 ) 2 , [CH 3 O(CH 2 ) 3 ] 2 —P—CH 2 CH 2 —N(CH 2 CH 2 OCH 3 )—CH 2 CH 2 —P—[(CH 2 ) 3 OCH 3 ] 2  and (CH 3 CH 2 OCH 2 CH 2 ) 2 —P—CH 2 CH 2 —N(CH 2 CH 2 OCH 3 )—CH 2 CH 2 CH 2 —P—(CH 2 CH 2 OCH 2 CH 3 ) 2 .  
     
     
         20 . A process according to any one of  claims 14  to  17 , wherein said diphosphine compound is selected from the group consisting of bis(diphenylphosphinoethyl)dioxyethylene, bis(dimethoxyphosphinoethyl)dioxyethylene, bis(diphenylphosphinoethyl)ether, bis(diphhenylphosphinoethyl)sulfide and bis(diphenylphosphinoethyl)alkylene.  
     
     
         21 . A process according to any one of  claims 14  to  20 , wherein said bidentate ligand Y is a bidentate ligand having a combination of electron-donating atoms selected from the group consisting of [N − , S − ], [O − , S − ], [S − , S − ], [N − , S], [N, S − ], [O, S − ], [O, O − ],[O, N − ], [N − , N − ], [O − , S], [O − , O − ], [O − , N], [S, S − ], [N, N − ], [O, N − ], [O, N], [N, N], [S, S], [O, O], [N, S] and [O, S].  
     
     
         22 . A process according to any one of  claims 14  to  21 , wherein said bidentate ligand is physiologically active.  
     
     
         23 . A process according to any one of  claims 14  to  22 , wherein said bidentate ligand Y comprises a combination of a physiologically active substance selected from the group consisting of a sugar, an amino acid, a fatty acid, a hormone, a peptide and a receptor-attachable ligand, and said electron-donating atoms.  
     
     
         24 . A process according to  claim 22  or  23 , wherein said bidentate ligand is selected from the group consisting of 1-thio-β-D-glucose, thiosalicylic acid, cysteine, cystein ethyl ester, 2-aminoethanethiol, dithiocarbamic acid and derivatives thereof, and dithiocarbamic acid and derivatives thereof.  
     
     
         25 . A process according to  claim 24 , wherein said dithiocarbamic acid derivatives is one member selected from the group consisting of N-methyl-S-methyl dithiocarbamate, N-diethyl dithiocarbamate, N-ethyl dithiocarbazate and N-ethoxy-N-ethyl dithiocarbamate, or said dithiocarbazic acid derivatives is one member selected from the groups consisting of N-ethyl dithiocarbamate and N-methyl-S-methyl dithiocarbazate.  
     
     
         26 . A process according to any one of claims  14  to  24 , wherein the oxide of said radioactive transition metal M is selected from the group consisting of  99m TcO 4   − ,  186 ReO 4   −  and  188 ReO 4   − .