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 complexing 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) where 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 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.

1 . A kit which comprises (a) a lyophilized stannous ion reducing agent composition, (b) a metal selected from the group consisting of Mn,  99m Tc,  186 Re and  188 Re, and (c) carbon monoxide.  
     
     
         2 . The kit of  claim 1  wherein said stannous ion 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 .  
     
     
         3 . The kit of  claim 1  wherein said stannous ion reducing agent is SnCl 2 .  
     
     
         4 . The kit of  claim 1  wherein said stannous ion reducing agent composition further comprises a stabilizing agent.  
     
     
         5 . The kit of  claim 4  wherein said stabilizing agent is pyrophosphate.  
     
     
         6 . The kit of  claim 4  wherein said stabilizing agent is gluceptate.  
     
     
         7 . The kit of  claim 1  wherein said stannous ion reducing agent composition further comprises lactose.  
     
     
         8 . The kit of  claim 1 , wherein said stannous ion reducing agent composition is sealed in a container having a headspace comprising carbon monoxide.  
     
     
         9 . The kit of  claim 8  wherein said carbon monoxide is substantially pure carbon monoxide.  
     
     
         10 . The kit of  claim 1  which further comprises an aminopolycarboxylate ligand.  
     
     
         11 . A kit of  claim 1  for carrying out 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 ligand L x  with a compound of formula  
   fac-[M(CO) 3 (OH 2 ) 3 ] +   (I)  
 wherein M is as defined above, and wherein the compound of formula (I) is prepared by reacting a metal in permetallate form with carbon monoxide and a stannous ion reducing agent.  
 
     
     
         12 . A kit for reducing a metal selected from the group consisting of Mn,  99m Tc,  186 Re and  188 Re, which comprises (a) said metal in permetallate form; (b) a lyophilized stannous ion formulation which comprises stannous ion and an anion; and (c) carbon monoxide.  
     
     
         13 . The kit of  claim 12  wherein said stannous ion reducing agent composition further comprises a stabilizing agent.  
     
     
         14 . The kit of  claim 13  wherein said stabilizing agent is pyrophosphate.  
     
     
         15 . The kit of  claim 13  wherein said stabilizing agent is gluceptate.  
     
     
         16 . The kit of  claim 12  wherein said stannous ion reducing agent composition further comprises lactose.  
     
     
         17 . The kit of  claim 12 , wherein said stannous ion reducing agent composition is sealed in a container having a headspace comprising carbon monoxide.  
     
     
         18 . The kit of  claim 17  wherein said carbon monoxide is substantially pure carbon monoxide.  
     
     
         19 . The kit of  claim 12  which further comprises an aminopolycarboxylate ligand.  
     
     
         20 . A kit of  claim 12  for carrying out 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 ligand L x  with a compound of formula  
   fac-[M(CO) 3 (OH 2 ) 3 ] +   (I)  
 wherein M is as defined above, and wherein the compound of formula (I) is prepared by reacting a metal in permetallate form with carbon monoxide and a stannous ion reducing agent.  
 
     
     
         21 . A kit for reducing a metal selected from the group consisting of Mn,  99m Tc,  186 Re and  188 Re, which comprises: 
 (a) said metal in permetallate form and    (b) a lyophilized stannous ion reducing agent composition comprising 
 i) SnCl 2 ,  
 ii) pyrophosphate or gluceptate, and  
 iii) lactose,  
 wherein said stannous ion reducing agent composition is sealed in a container having a headspace comprising substantially pure carbon monoxide.