Small technetium-99m and rhenium labeled agents and methods for imaging tumors

Abstract

The present invention relates to compounds and related technetium and rhenium complexes thereof which are suitable for imaging or therapeutic treatment of tumors, e.g., carcinomas, melanomas and other tumors. In another embodiment, the invention relates to methods of imaging tumors using radiolabeled metal complexes. Preferred radiolabeled complexes for imaging tumors include technetium and rhenium complexes. The high tumor uptake and significant tumor/nontumor ratios of the technetium complexes of the invention indicate that such small technetium-99m-based molecular probes can be developed as in-vivo diagnostic agents for melanoma and its metastases. In yet another embodiment, the invention relates to methods of treatment of tumors using a radiolabeled metal complex as a radiopharmaceutical agent to treat the tumor.

1 . A compound capable of binding a metal ion, the compound according to the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R A  is independently chosen at each occurrence of R A  from the group consisting of hydrogen, lower alkyl having 1 to about 4 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, and —XNR 1 R 2 ; 
 R B  is hydrogen for each occurrence of R B ; or 
 —(CR A R B )— taken in combination is —C═O— such that there are zero or one —C═O— groups; 
 R C  is independently selected at each occurrence of R C  from the group consisting of hydrogen, lower alkyl groups having 1 to about 8 carbon atoms, alkyl ester or aryl ester groups having about 2 to about 8 carbon atoms, alkyl amide or aryl amide groups having about 2 to 8 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, and —XNR 1 , R 2 ; 
 X is a linking group comprising a backbone chain having 1 to about 8 atoms, the backbone chain can optionally include ester, amide, amine, ether or thioether linkages in the backbone chain and does not include aromatic groups integral to the backbone chain of the linking group; and 
 R 1  and R 2  each are independently selected lower alkyl groups having 1 to about 4 carbon atoms; or 
 —NR 1 R 2  taken in combination is a heterocyclic ring having 3 to about 8 ring atoms and 1 or 2 hetero ring atoms; 
 n is either 2 or 3 and is independently chosen at each occurrence of n; and 
 at least one occurrence of R A  or R C  in Formula I is chosen to be —XNR 1 R 2 , 
 where the radiolabeled complex resulting from the binding of the compound to the metal ion is either neutral or cationic. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is capable of binding a metal ion selected from the group consisting of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum and rhodium. 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein NR 1 R 2  taken in combination form a heterocyclic ring having 5, 6 or 7 ring atoms. 
     
     
         5 . The compound of  claim 4 , wherein the heterocyclic ring is a heterocycle according to the formula: 
       
         
           
           
               
               
           
         
         where A is CH 2 , NR D , O or S; 
         R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ; 
       
     
     
         6 . The compound of  claim 5 , wherein —NR 1 R 2  taken in combination is N-morpholino or N-piperidinyl. 
     
     
         7 . The compound of  claim 1 , according to the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  each are independently selected from lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
           R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ; 
         
         X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
         m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
         q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
       
     
     
         8 . The compound of  claim 1 , according go the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is lower alkyl group having 1 to about 8 carbon atoms, alkoxyalkyl groups having 2 to about 8 carbon atoms, or aralkyl groups having 6 to about 2 carbon atoms; 
         R 1  and R 2  each are independently selected from lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
         
       
       R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ;
 X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
 m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
 q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
 
     
     
         9 . The compound of  claim 1 , according go the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  each are independently selected from lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
         
       
       R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ;
 X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
 m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
 q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
 
     
     
         10 . A neutral or cationic radiolabeled complex comprising a compound of  claim 1  and a metal ion. 
     
     
         11 . A neutral or cationic radiolabeled complex of  claim 10 , wherein the metal ion is selected from the group consisting of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum and rhodium. 
     
     
         12 . (canceled) 
     
     
         13 . A radiolabeled complex of  claim 10 , wherein the complex is of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  each are independently selected from a lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
         
       
       R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ;
 X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
 m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
 q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
 
     
     
         14 . A radiolabeled complex of  claim 10 , wherein the complex is of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  each are independently selected from a lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
         
       
       R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ;
 X is —(CH 2 ) q —, (CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
 m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
 q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
 
     
     
         15 . A method for in-vivo or in-vitro imaging of at least one tumor comprising the steps of:
 providing a radiolabeled complex comprising a metal ion and a compound of the following structure:
   Y—X—NR 1 R 2    
   
       wherein
 Y is a chelating ligand capable of binding the metal ion; 
 X is a linking group comprising a backbone chain having 1 to about 8 atoms, the backbone chain can optionally include ester, amide, amine, ether or thioether linkages in the backbone chain and does not include aromatic groups integral to the backbone chain of the linking group; and 
 R 1  and R 2  each are independently selected from a lower alkyl group having 1 to about 4 carbon atoms, or 
 —NR 1 R 2  taken in combination is a heterocyclic ring having 3 to about 8 ring atoms and 1 or 2 hetero ring atoms; 
 contacting the tumor(s) with the radiolabeled metal complex; and 
 making a radiographic image to image the tumor(s). 
 
     
     
         16 . A method of  claim 15 , wherein the metal ion is selected from the group consisting of technetium, rhenium, yttrium, copper, gallium, indium, bismuth, platinum and rhodium. 
     
     
         17 .- 21 . (canceled) 
     
     
         22 . A method of  claim 15 , wherein Y is a tetradentate chelating ligand capable of binding technetium-99m or at least one isotope of rhenium. 
     
     
         23 . A method of  claim 22 , wherein the tetradentate chelating ligand, Y, is an amido-amino-dithiolate or diamino-dithiolate and the nitrogen and sulfur atoms capable of binding technetium are linked by ethylene or propylene groups wherein each carbon of the ethylene or propylene linker groups are substituted with one or more substituents chosen from the group consisting of hydrogen, lower alkyl having 1 to about 4 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, oxo, and —XNR 1 R 2 . 
     
     
         24 . A method of  claim 23 , wherein NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
         
           
           
               
               
           
         
         where A is CH 2 , NR D , O or S; 
         R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 . 
       
     
     
         25 . A method of  claim 23 , wherein the compound of the formula Y—X—NR 1 R 2  is a compound of the formula: 
       
         
           
           
               
               
           
         
         R A  and R B  are independently chosen at each occurrence of R A  and R B  in the ligand from the group consisting of hydrogen, lower alkyl having 1 to about 4 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, and —XNR 1 R 2 ; or 
         —(CR A R B )— taken in combination is —C═O—; 
         R C  is independently selected at each occurrence of R C  from the group consisting of hydrogen, lower alkyl groups having 1 to about 8 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, and —XNR 1 R 2 ; 
         X is a linking group comprising a backbone chain having 1 to about 8 atoms, the backbone chain can optionally include ester, amide, amine, ether or thioether linkages in the backbone chain and does not include aromatic groups integral to the backbone chain of the linking group; and 
         R 1  and R 2  each are independently selected from lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
         
         R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ; 
         n is either 2 or 3 and is independently chosen at each occurrence of n; and 
         at least one occurrence of R A  or R C  in Formula I is chosen to be XNR 1 R 2 , 
         where the radiolabeled complex resulting from the binding of the compound to the metal ion is either neutral or cationic. 
       
     
     
         26 . A method of  claim 25 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  each are independently selected from lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
           R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ; 
         
         X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
         m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
         q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
       
     
     
         27 . A method of  claim 25 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is lower alkyl group having 1 to about 8 carbon atoms, alkoxyalkyl groups having 2 to about 8 carbon atoms, or aralkyl groups having 6 to about 2 carbon atoms; 
         R 1  and R 2  each are independently selected from lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
         
       
       R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ;
 X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
 m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
 q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
 
     
     
         28 . A method of  claim 25 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  each are independently selected from lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
         
       
       R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ;
 X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
 m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
 q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
 
     
     
         29 . A method of  claim 25 , wherein the radiolabeled complex is of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  each are independently selected from a lower alkyl group having 1 to about 4 carbon atoms; or 
         —NR 1 R 2  taken in combination is a heterocyclic ring according to the formula: 
       
       
         
           
           
               
               
           
         
         
           where A is CH 2 , NR D , O or S; 
           R D  is chosen from the group consisting of hydrogen, lower alkyl group having from 1 to about 4 carbon atoms, aralkyl groups having from 7 to about 18 carbon atoms, aryl groups having 6 to about 18 carbon atoms, alkyl ester groups having about 2 to about 8 carbon atoms, aryl ester groups having about 7 to about 18 carbon atoms, alkyl amide groups having about 2 to about 8 carbon atoms, aryl amide groups having about 7 to about 18 carbon atoms, di(alkyl)aminoalkyl groups where each alkyl group has 1 to about 4 carbon atoms, —XNR 1 R 2 ; 
         
         X is —(CH 2 ) q —, —(CH 2 ) m C(O)NH—(CH 2 ) p —, —(CH 2 ) m C(O)O—(CH 2 ) p —; 
         m and p are independently chosen at each occurrence of m and p to be 1 to about 3; and 
         q is independently chosen at each occurrence of q to be a number from 1 to about 6. 
       
     
     
         30 . (canceled) 
     
     
         31 . A method for the for treatment of cancer comprising the steps of:
 providing a cytotoxic metal complex comprising a metal ion and a compound of the following structure:
   Y—X—NR 1 R 2    
   wherein
 Y is a chelating ligand capable of binding the metal ion; 
 X is a linking group comprising a backbone chain having 1 to about 8 atoms, the backbone chain can optionally include ester, amide, amine, ether or thioether linkages in the backbone chain and does not include aromatic groups integral to the backbone chain of the linking group; and 
 R 1  and R 2  each are independently selected from a lower alkyl group having 1 to about 4 carbon atoms, or 
 —NR 1 R 2  taken in combination is a heterocyclic ring having 3 to about 8 ring atoms and 1 or 2 hetero ring atoms; and 
 contacting the tumor(s) with the cytotoxic metal complex. 
   
     
     
         32 .- 34 . (canceled)