Formulation of Tc and Re carbonyl complexes using stannous ion as the reductant for pertechnetate and perrhenate

Abstract

The invention relates to novel aminocarboxylate ligands that are suitable for completing with a radionuclide, and are useful as therapeutic agents and as imaging agents for diagnostic purposes. In accordance with the present invention, a method of preparing a compound of formula fac -[M(CO) 3 (OH 2 ) 3 ] +   (I) wherein M is Mn, 99m Tc, 186 Re or 188 Re, involves reacting a metal in permetallate form with carbon monoxide and stannous ion. The compound of formula (I) can be reacted with a ligand L x to form a compound of the formula i fac-[M(CO) 3 L x ] n   (II) wherein M is as defined above, L x is a monodentate or multidentate ligand or a mixture of these ligands, and n is a charge of the ligand L x increased with one+charge. The invention also is directed to novel compounds, and kits for carrying out the disclosed methods.

What is claimed is:  
     
         1 . A method of preparing a compound of formula 
         fac -[M(CO) 3 (OH 2 ) 3 ] +   (I) wherein M is Mn,  99m Tc,  186 Re or  188 Re, comprising reacting a metal in permetallate form with carbon monoxide and a reducing agent, wherein said reducing agent comprises stannous ion.    
     
     
         2 . The method of  claim 1  wherein said mixture further includes a stabilizing agent.  
     
     
         3 . The method of  claim 1  wherein said reducing agent forms a stannous ion.  
     
     
         4 . The method of  claim 1  wherein said reducing agent is a stannous salt.  
     
     
         5 . The method of  claim 1  wherein said reducing agent is selected from the group consisting of SnCl 2 , SnCl 2 H 2 O, SnF 2 , SnBr 2 , SnCl 2 O, SnI 2 , and SnSO 4 .  
     
     
         6 . The method of  claim 1  wherein said mixture further includes lactose.  
     
     
         7 . The method of  claim 1  wherein said mixture further includes pyrophosphate or gluceptate.  
     
     
         8 . A method of preparing a compound of formula 
         fac -[M(CO) 3 L x ] n   (II) 
       wherein: 
 M is Mn,  99m Tc,  186 Re or  188 Re;  
 L x  is i) three monodentate ligands ii) one monodentate ligand and one bidentate ligand, or iii) one tridentate ligand; and  
 n is a charge of the ligand L x  increased with one+charge;  
 comprising reacting a compound of formula (I) prepared according to  claim 1  with ligand L x .  
 
     
     
         9 . The method of  claim 8 , wherein the reaction with ligand L x  takes place in the presence of a halide or a halide-like salt.  
     
     
         10 . The method of  claim 9  wherein said halide-like salt is selected from the group consisting of acetates, phosphates and sulfates.  
     
     
         11 . The method of  claim 8  wherein L x  comprises an aminopolycarboxylate.  
     
     
         12 . The method of  claim 8  wherein L x  comprises a biologically active substrate selected from the group consisting of amino acids, peptides, proteins, sugars, small receptor binding molecules and body cells.  
     
     
         13 . The method of  claim 8  wherein said method is performed between about 20° C. and 150° C.  
     
     
         14 . The method of  claim 8  wherein said method is performed at about 100° C.  
     
     
         15 . The method of  claim 11  wherein said aminopolycarboxylate ligand is selected from the group consisting of diethylenetriamine-pentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), and triazacyclononanetriacetate.  
     
     
         16 . The method of  claim 11  wherein said ligand is not bidentate.  
     
     
         17 . The method of  claim 11  wherein said ligand is tridentate.  
     
     
         18 . A kit for carrying out the method of  claim 1 , comprising a lyophilized formulation including stannous ion, wherein said stannous ion may be in the form of a discrete molecule comprising said stannous ion plus an anion, said mixture being sealed in a container having a headspace comprising carbon monoxide.  
     
     
         19 . The kit of  claim 18  wherein said headspace is substantially pure carbon monoxide.  
     
     
         20 . The kit of  claim 18  wherein said reducing agent forms a stannous ion.  
     
     
         21 . The kit of  claim 18  wherein said reducing agent is a stannous salt.  
     
     
         22 . The kit of  claim 18  wherein said reducing agent is selected from the group consisting of SnCl 2 , SnCl 2 H 2 O, SnF 2 , SnBr 2 , SnCl 2 2H 2 O, SnI 2 , and SnSO 4 .  
     
     
         23 . The kit of  claim 18  wherein said reducing agent is SnCl 2 .  
     
     
         24 . The kit of  claim 18  wherein said formulation further includes lactose.  
     
     
         25 . The kit of  claim 18  wherein said formulation further includes pyrophosphate or gluceptate.  
     
     
         26 . The kit of  claim 18  further including a metal M which is Mn,  99m Tc,  186 Re or  188 Re.  
     
     
         27 . A kit for carrying out the method of  claim 8 , comprising a lyophilized formulation including stannous ion, wherein said stannous ion may be in the form of a discrete molecule comprising said stannous ion plus an anion, and a metal M which is Mn,  99m Tc,  186 Re or  188 Re.  
     
     
         28 . The kit of  claim 27  wherein said reducing agent is SnCl 2 .  
     
     
         29 . The kit of  claim 27  wherein said formulation further includes lactose.  
     
     
         30 . The kit of  claim 27  wherein said formulation further includes pyrophosphate or gluceptate.  
     
     
         31 . The kit of  claim 27  further comprising a ligand L x  which is a multidentate aminopolycarboxylate ligand.  
     
     
         32 . The kit of claim  31  wherein L x  is not a bidentate ligand.