Multinuclear complexes and their preparation

Abstract

Multinuclear complexes and methods for preparing them are provided. The discrete multinuclear complexes include a one or more transition metals and a radioisotope having the same coordination geometry as the transition metal. A bridging ligand is coordinated to the transition metal and the radioisotope to link the transition metal and the radioisotope and pendent ligands are coordinated to each of the transition metal and the radioisotope to stabilise the complex. The multinuclear complexes may include a radioisotope or radioelement that can be detected by medical equipment and may find use in therapy and/or the diagnosis of disease in patients.

1 - 36 . (canceled) 
     
     
         37 . A multinuclear complex comprising:
 a transition metal;   a radioisotope having the same coordination number as the transition metal, wherein the radioisotope is an isotope of a transition metal or an isotope of an element of the same group in the periodic table as the transition metal;   a bridging ligand coordinated to the transition metal and the radioisotope to link the transition metal and the radioisotope; and   pendent ligands coordinated to each of the transition metal and the radioisotope.   
     
     
         38 . The multinuclear complex as claimed in  claim 37 , wherein the radioisotope is technetium-99m ( 99m Tc), rhenium-186 ( 186 Re) or rhenium-188 ( 188 Re). 
     
     
         39 . The multinuclear complex as claimed in  claim 37 , wherein the transition metal is selected from the group consisting of manganese (Mn), technetium (Tc) and rhenium (Re). 
     
     
         40 . The multinuclear complex as claimed in  claim 39 , wherein when the transition metal is rhenium, the transition metal is a β-radiation emitting isotopes of rhenium selected from rhenium-186 ( 186 Re) or rhenium-188 ( 188 Re), and when the transition metal is technetium, the transition metal is the technetium-99 ( 99 Tc) isotope. 
     
     
         41 . The multinuclear complex as claimed in  claim 37 , having the general formula [ 99m TcM(μ 2 -L) 2 (CO) 6 ], wherein
 M is Mn, Re or Tc, and 
 μ 2 -L is a bidentate bridging ligand having at least two coordinating atoms independently selected from the group consisting of an oxygen atom, a sulphur atom, a selenium atom, a nitrogen atom, a carbon atom and a phosphorus atom, wherein one of the coordinating atoms of the bidentate ligand coordinates to both  99m Tc and M as a bridging coordinating atom and the other coordinating atom of the same bidentate ligand coordinates to one of  99m Tc or M. 
 
     
     
         42 . The multinuclear complex as claimed in  claim 41 , wherein the bidentate ligand (μ2-L) is a Schiff base chelator. 
     
     
         43 . The multinuclear complex as claimed in  claim 41 , having the general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         M is Mn, Re or Tc, and
 R a , R b  and R c  are each independently a hydrogen, a C1-C10 linear or branched alkyl, an aryl, a heteroaryl, a poly(aryl), a poly(heteroaryl), a C5-C10 carbocyclyl or a heterocyclyl group, 
 or R a  and R b  together is a cyclic aromatic hydrocarbon, an aromatic heterocycle, a substituted polycyclic aromatic hydrocarbon, a polycyclic aromatic heterocycle, a cyclic or polycyclic hydrocarbon, a heterocycle, or a polyheterocycle, 
 or R a , R b  and R c  together is a polycyclic aromatic hydrocarbon, a polycyclic aromatic heterocycle, a polycyclic hydrocarbon or a polyheterocycle. 
 
       
     
     
         44 . The multinuclear complex as claimed in  claim 37  having the general formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         M is Mn, Re or Tc, 
         A is oxygen, sulfur or selenium; and
 R a , R b  and R c  are each independently a hydrogen, an C1-C10 linear or branched alkyl, an aryl, a heteroaryl, a poly(aryl), a poly(heteroaryl), a C5-C10 carbocyclyl or a heterocyclyl group, 
 or R a  and R b  together is a cyclic aromatic hydrocarbon, a aromatic heterocycle, a polycyclic aromatic hydrocarbon, a polycyclic aromatic heterocycle, a cyclic or polycyclic hydrocarbon, a heterocycle or polyheterocycle, 
 or R a , R b  and R c  together is a polycyclic aromatic hydrocarbon, a polycyclic aromatic heterocycle, a polycyclic hydrocarbon, or a polyheterocycle. 
 
       
     
     
         45 . The multinuclear complex as claimed in  claim 43 , wherein the halogen is selected from the group consisting of fluorine, chlorine, bromine and iodine
 and/or wherein the polycyclic aromatic hydrocarbon is selected from the group consisting of naphthalene, biphenyl, anthracene and phenanthrene   and/or wherein a pendent functional group on the aromatic structure of the polycyclic aromatic hydrocarbon includes one or more hetero atoms selected from the group consisting of oxygen, nitrogen, sulphur, selenium and phosphorus.   
     
     
         46 . The multinuclear complex as claimed in  claim 43 , wherein one or more R a , R b  and R c  alone or together is functionalized with a biologically active functionality of known affinity for a selected receptor. 
     
     
         47 . The multinuclear complex as claimed in  claim 37  having the general formula (II): 
       
         
           
           
               
               
           
         
         wherein M is Mn, Re or Tc, R 1  is an m-toluene group, a cyclopentane group, or an ethylbenzene group and R 2  is hydrogen or a methyl group. 
       
     
     
         48 . The multinuclear complex as claimed in  claim 41 , wherein the bidentate ligand (μ 2 -L) is a quinoline-based chelator. 
     
     
         49 . The multinuclear complex as claimed in  claim 48  having the general formula (IV) 
       
         
           
           
               
               
           
         
         wherein 
         M is Mn, Re or Tc; 
         A is oxygen, sulfur or selenium; and
 R 2a  to R 7a  are each independently a hydrogen, halogen, nitro, nitrile, amine, carboxylate, aldehyde, a C1-C10 linear or branched alkyl, an aryl, a heteroaryl, a poly(aryl), a poly(heteroaryl), a C5-C10 carbocyclyl or a heterocyclyl group, 
 or R 2a  to R 7a  together is a polycyclic aromatic hydrocarbon, a polycyclic aromatic heterocycle, a polycyclic hydrocarbon, or a polyheterocycle. 
 
       
     
     
         50 . The multinuclear complex as claimed in  claim 37  having the general formula [ 99m TcM 2 O 2 (μ_L) 2 (LL) 6 ], wherein
 M is Mn, Re or Tc; 
 μ_L is a bridging ligand selected from oxides (O 2− ) or sulphides (S 2− ); and 
 LL is a bidentate pendent ligand separately coordinated to each of  99m Tc and M and having at least two coordinating atoms independently selected from the group consisting of an oxygen atom, a sulphur atom, a selenium atom, a nitrogen atom, a carbon atom and a phosphorus atom. 
 
     
     
         51 . The multinuclear complex as claimed in  claim 50  having the general formula (V): 
       
         
           
           
               
               
           
         
         wherein 
         at least one of M 1 , M 2  or M 3  is  99m Tc and the remaining metal centres of M 1 , M 2  or M 3  are Mn, Re or Tc or any combination thereof; 
         A is an oxygen, sulfur or selenium atom; and
 R 2a  to R 7a  are each independently a hydrogen, halogen, nitro, nitrile, amine, carboxylate, aldehyde, a C1-C10 linear or branched alkyl, an aryl, a heteroaryl, a poly(aryl), a poly(heteroaryl), a C5-C10 carbocyclyl or a heterocyclyl group, 
 or R 2a  to R 7a  together is a polycyclic aromatic hydrocarbon, a polycyclic aromatic heterocycle, a polycyclic hydrocarbon, or a polyheterocycle. 
 
       
     
     
         52 . The multinuclear complex as claimed in  claim 49 , wherein one or more of R 2a  to R 7a , separately or together, is a biologically active functionality of known affinity for a selected receptor
 or wherein R 2a  is an amino group (—NH 2 ) and R 3a  to R 7a  are hydrogen; or R 2a  to R 4a  and R 6a  are hydrogen and R 5a  and R 7a  are chlorine and; or R 2a  to R 6a  are hydrogen and R 7a  is a thiol (—SH).   
     
     
         53 . The multinuclear complex as claimed in  claim 37 , having the general formula: [ 99m TcM 3 (L) 4 (CO) 12 ], wherein M is Mn, Re or Tc, and L is a bridging ligand having a coordinating atom selected from the group consisting of an oxygen atom, a sulfur atom, and a selenium atom. 
     
     
         54 . The multinuclear complex as claimed in  claim 53 , having a cubane structure and the general formula (VI): 
       
         
           
           
               
               
           
         
         wherein M is Mn, Re or Tc and L is a monodentate bridging ligand having a coordinating atom selected from the group consisting of an oxygen atom, a sulfur atom, and a selenium atom 
         and/or wherein the bridging ligands (L) are selected from the group consisting of hydroxides (OH − ), thiols (SH − ), C1-C10 alkoxides, C1-C10 thiolates and C1-C10 selenolates, 
         wherein the C1-C10 alkoxides, C1-C10 thiolates and C1-C10 selenolates are functionalised with a bioactive or targeting moiety. 
       
     
     
         55 . The multinuclear complex as claimed in  claim 54 , having the molecular formula [ 99m TcRe 3 (μ 2 _OH) 4 (CO) 12 ] and the structural formula (VII): 
       
         
           
           
               
               
           
         
       
     
     
         56 . A method of preparing a multinuclear complex by self-assembly in solution comprising:
 mixing a multinuclear or mononuclear precursor complex of a transition metal with a mononuclear complex that includes a radioisotope of the same coordination number as the transition metal in a selected solvent.   
     
     
         57 . The method as claimed in  claim 56 , wherein the multinuclear or mononuclear precursor complex of a transition metal is anionic and the mononuclear complex that includes the radioisotope is cationic in solution and both the precursor complex and the complex including the radioisotope have octahedral coordination geometry,
 and/or wherein the radioisotope is technetium-99m ( 99m Tc) and the transition metal is selected from the group consisting of manganese technetium and rhenium,   and/or wherein the mononuclear precursor complex has the general molecular formula fac-[M(X) 3 (CO) 3 ] 2−  in solution, wherein M is Mn, Re or Tc, X is Br when M is Re and X is Cl when M is Tc and the mononuclear complex including a radioisotope has the general molecular formula [ 99m Tc(Y) 3 (CO) 3 ] +  in solution, wherein Y is as neutral ligand selected from water (OH 2 ) or a solvent molecule,   and/or wherein the solvent is water, alcohol, acetonitrile, acetone or dimethylsulfoxide,   and/or wherein the mixing occurs in the presence of a bidentate ligand to form the multinuclear complex, the transition metal selected from the group consisting of manganese (Mn), technetium (Tc) and rhenium (Re), wherein:
 when the transition metal is rhenium, the transition metal is a β-radiation emitting isotope of rhenium selected from rhenium-186 ( 186 Re-) or rhenium-188 ( 188 Re), and 
 when the transition metal is technetium the transition metal is the technetium-99 ( 99 Tc) isotope. 
   
     
     
         58 . The method as claimed in  claim 56 , wherein:
 the multinuclear complex has the general formula [ 99m TcM(μ 2 -L) 2 (CO) 6 ], M is Mn, Re or Tc,   μ 2 -L is a bidentate bridging ligand having at least two coordinating atoms independently selected from the group consisting of an oxygen atom, a sulphur atom, a selenium atom, a nitrogen atom, a carbon atom and a phosphorus atom, wherein one of the coordinating atoms of the bidentate ligand coordinates to both  99m Tc and M as a bridging coordinating atom and the other coordinating atom of the same bidentate ligand coordinates to one of  99m Tc or M   the multinuclear complex is formed:
 in one step by adding the mononuclear precursor complex of the general molecular formula, fac-[M(Z) 3 (CO) 3 ] + , wherein M is Mn, Re or Tc and Z is a protonated monodentate bridging ligand (H-L), to a solution of the mononuclear complex of the general molecular formula fac-[ 99m Tc(Z) 3 (CO) 3 ] + , wherein Z is a protonated monodentate bridging ligand (H-L) and mixing the resultant solution; or 
 by preassembly of a multinuclear precursor complex in the form of an anionic trinuclear complex that leaves a vertex for the coordination of the complex including the radioisotope, the trinuclear complex having the general molecular formula [M 3 (μ 2 _L) 3 (μ 3 _L)(CO) 9 ] − , wherein M is Mn, Re or Tc and μ 2 _L is a monodentate ligand selected from the group consisting of hydroxides (OH − ), thiols (SH − ), C1-C10 alkoxides, C1-C10 thiolates and C1-C10 selenolates coordinated to two metal centres and μ 3 _L is a monodentate ligand selected from the group consisting of hydroxides (OH − ), thiols (SH − ), C1-C10 alkoxides, C1-C10 thiolates and C1-C10 selenolates coordinated to three metal centres and adding the anionic trinuclear complex to a solution of the mononuclear complex of the general molecular formula fac-[ 99m Tc(Z) 3 (CO) 3 ] + , wherein Z is a protonated monodentate bridging ligand (H-L) of the tetranuclear complex, and for the resultant solution to be mixed. 
   
     
     
         59 . The method as claimed in  claim 58 , wherein the pH of the solution of the mononuclear complex of the general molecular formula fac-[ 99m Tc(Z) 3 (CO) 3 ] +  is adjusted to be about 5, prior to mixing
 and/or wherein Z is OH 2  and the solution is an aqueous solution. 
 
     
     
         60 . A pharmaceutical composition comprising a multinuclear complex as claimed in  claim 37  and a diluent, excipient or carrier.