Polypodal chelants for metallopharmaceuticals

Abstract

Tripodal polyaminophosphonate chelants are disclosed, as well as chelates of the chelants with metal ions to form radiopharmaceutical and radioactive, MRI and X-ray or CT imaging compounds and compositions. Therapeutic and imaging methods of use are also disclosed.

1 . A tripodal polyaminophosphonate chelant having the formula:  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein 
 A is selected from the group consisting of CR 3 , SiR 3 , GeR 3 , N, P, P═O, P═S, As, As═O, and a macrocyclic group having the formula: 
   —[C(L)R 12 (CR 13 R 14 ) a ] b —, —[N(L)C(W)(CR 15 R 16 ) c ] d —, —[OC(W)C(L)R 17 (CR 18 R 19 ) e ] f — or —{[NR 20 C(W)C(L)R 21 (CR 22 R 23 ) g ] h [NR 24 C(W)(CR 25 R 16 ) i ] j }—, 
 wherein  
 a is an integer selected from 1 to 3;  
 b is an integer selected from 3 to 5;  
 c is an integer selected from 1 to 3;  
 d is an integer selected from 3 or 4;  
 e is an integer selected from 1 to 3;  
 f is an integer selected from 3 or 4;  
 g is an integer selected from 1 to 3;  
 h is an integer selected from 3 or 4;  
 i is an integer selected from 1 to 3;  
 j is an integer selected from 0 to 3;  
 L is a direct bond to X;  
 W is H 2  or O;  
 R 1  is (CR 4 R 5 ) n R 6 , wherein n is an integer selected from 0 to 3;  
 R 2  is selected from the group consisting of C 1 -C 10  fluoroalkyl substituted with 0-5 R 7 , C 2 -C 10  alkenyl substituted with 0-5 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-5 R 7 , aryl substituted with 0-5 R 7 , heteroaryl substituted with 0-5 R 7  and fluoroaryl substituted with 0-5 R 7 ;  
 R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-5 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-5 R 7 , C 2 -C 10  alkenyl substituted with 0-5 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-5 R 7 , aryl substituted with 0-5 R 7 , heteroaryl substituted with 0-5 R 7  and fluoroaryl substituted with 0-5 R 7 ; or R 4  and R 5  may be taken together to form a C 3 -C 10  cycloalkyl or C 3 -C 10  cycloalkenyl optionally interrupted with C(O)NH, NH, NHC(O), NHC(O)NH, NHC(S)NH, O, S, S(O), S(O) 2 , P(O)(OR 8 ), P(O)(OR 8 )O, P(O)(NHR 7 )O, or to form an aryl substituted with 0-5 R 7 , a fluoroaryl substituted with 0-5 R 7  or an N-containing heterocycle substituted with 0-5 R 7 ;  
 R 7  is selected from the group consisting of H, OH, C(═O)R 8 , C(═O)OR 8 , C(═O)NR 8   2 , PO(OR 8 ) 2  and S(O) 2 OR 8 ;  
 R 8  is selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  fluoroalkyl, C 1 -C 6  alkenyl, C 3 -C 6  cycloalkyl, C 1 -C 6  fluoroalkenyl, benzyl, fluorobenzyl, phenyl and fluorophenyl;  
 X is selected from the group consisting of (CR 9 R 10 ) m , NR 11 , and O(CR 9 R 10 ) m , wherein m is an integer selected from 1 to 3, provided that when A is N or —[N(L)C(W)(CR 15 R 16 ) c ] d —, X is (CR 9 R 10 ) m ;  
 R 9 , R 10  and R 11  are independently selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-5 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-5 R 7 , C 2 -C 10  alkenyl substituted with 0-5 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-5 R 7 , aryl substituted with 0-5 R 7  and fluoroaryl substituted with 0-5 R 7 ; or R 9  and R 10  may be taken together to form a C 3 -C 10  cycloalkyl or C 3 -C 10  cycloalkenyl optionally interrupted with C(O)NH, NH, NHC(O), NHC(O)NH, NHC(S)NH, O, S, S(O), S(O) 2 , P(O)(OR 8 ), P(O)(OR 7 )O, P(O)(NHR 7 )O, or to form an aryl substituted with 0-5 R 8  or fluoroaryl substituted with 0-5 R 8 ; and  
 R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , and R 26  are independently selected at each occurrence from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  fluoroalkyl, C 1 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 1 -C 6  fluoroalkenyl, benzyl, fluorobenzyl, phenyl and fluorophenyl.  
 
     
     
         2 . A tripodal polyaminophosphonate chelant according to  claim 1 , wherein: 
 A is selected from the group consisting of CR 3 , N and P═O;    R 1  is (CH 2 ) n R 6 ;    R 3  and R 6  are independently selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7 , fluroaryl substituted with 0-2 R 7  and heteroaryl substituted with 0-2 R 7 ;    X is selected from the group consisting of (CH 2 ) m , NR 11  and O(CR 9 R 10 ) m , wherein m is an integer selected from 1 to 3, provided that when A is N, X is (CH 2 ) m ; and    R 11  is selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7  and fluroaryl substituted with 0-2 R 7 .    
     
     
         3 . A tripodal polyaminophosphonate chelant according to  claim 2 , wherein: 
 A is CR 3  or N;    n is 0 or 1;    R 3  is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  fluoroalkyl, C 2 -C 10  alkenyl, C 2 -C 10  fluoroalkenyl, aryl and fluoroaryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, C(═O)NH 2 , PO(OH) 2  and S(O) 2 OH; and    X is (CH 2 ) m , wherein m is 1 or 2.    
     
     
         4 . A tripodal polyaminophosphonate chelant according to  claim 3 , wherein: 
 A is CR 3  or N;    R 3  is selected from the group consisting of H, C 1 -C 10  alkyl and C 1 -C 10  aryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, PO(OH) 2  and S(O) 2 OH; and    X is (CH 2 ) m , wherein m is 1 or 2.    
     
     
         5 . (cancelled)  
     
     
         6 . (cancelled)  
     
     
         7 . The tripodal polyaminophosphonate chelant of  claim 1 , wherein the phosphorous atoms in said chelant comprise  32 P.  
     
     
         8 . A radiopharmaceutical compound comprising a tripodal polyaminophosphonate chelant according to  claim 1 , chelated with a radionuclide selected from the group consisting of  52m Mn,  52 Fe,  55 Co,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  90 Y,  94m Tc,  99m Tc,  105 Rh,  109 Pd,  111 In,  117m Sn,  149 Pr,  153 Sm,  159 Gd,  166 Ho,  169 Yb,  177 Lu,  186 Re, 188Re,  203 Pb,  211 Pb, and  212 Bi.  
     
     
         9 . A radiopharmaceutical compound according to  claim 8 , wherein: 
 A is selected from the group consisting of CR 3 , N and P═O;    R 1  is (CH 2 ) n R 6 ;    R 3  and R 6  are independently selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7 , fluoroaryl substituted with 0-2 R 7  and    heteroaryl substituted with 0-2 R 7 ;    X is selected from the group consisting of (CR 9 R 10 ) m , NR 11 , and O(CR 9 R 10 ) m , wherein m is an integer selected from 1 to 3, provided that when A is N, X is (CR 9 R 10 ) m ;    R 11  is selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7  and fluoroaryl substituted with 0-2 R 7 .    
     
     
         10 . A radiopharmaceutical compound according to  claim 9 , wherein: 
 A is CR 3  or N;    n is 0 or 1;    R 3  is independently selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  fluoroalkyl, C 2 -C 10  alkenyl, C 2 -C 10  fluoroalkenyl, aryl and fluroaryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, C(═O)NH 2 , PO(OH) 2  and S(O) 2 OH; and    X is (CH 2 ) m , wherein m is 1 or 2.    
     
     
         11 . A radiopharmaceutical compound according to  claim 10 , wherein: 
 A is CR 3  or N;    R 3  is selected from the group consisting of H, C 1 -C 10  alkyl and C 1 -C 10  aryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, PO(OH) 2  and S(O) 2 OH; and    X is (CH 2 ) m , wherein m is 1 or 2.    
     
     
         12 . A radiopharmaceutical compound according to  claim 11 , having the formula:  
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of phenyl, benzyl, imidazolyl, pyridyl and thiophenyl, each substituted with 0-2 OH.  
       
     
     
         13 . A radiopharmaceutical compound according to  claim 12 , having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         14 . An MRI contrast agent comprising a tripodal polyaminophosphonate chelant according to  claim 1 , chelated with a paramagnetic metal ion of atomic number 21-29, 42-44 or 58-70.  
     
     
         15 . An MRI contrast agent according to  claim 14 , wherein: 
 A is selected from the group consisting of CR 3 , N and P═O;    R 1  is (CH 2 ) n R 6 ,    R 2  is selected from the group consisting of C 1 -C 10  fluoroalkyl substituted with 0-5 R 7 , C 2 -C 10  alkenyl substituted with 0-5 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-5 R 7 , aryl substituted with 0-5 R 7 , heteroaryl substituted with 0-5 R 7  and fluoroaryl substituted with 0-5 R 7 ;    R 3  and R 6  are independently selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7 , fluoroaryl substituted with 0-2 R 7  and heteroaryl substituted with 0-2 R 7 ;    X is selected from the group consisting of (CR 9 R 10 ) m , NR 11 , and O(CR 9 R 10 ) m , wherein m is an integer selected from 1 to 3, provided that when A is N, X is (CR 9 R 10 ) m ;    R 11  is selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7  and fluroaryl substituted with 0-2 R 7 .    
     
     
         16 . An MRI contrast agent according to  claim 15 , wherein: 
 A is CR 3  or N;    n is 0 or 1;    R 3  is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  fluoroalkyl, C 2 -C 10  alkenyl, C 2 -C 10  fluoroalkenyl, aryl and fluroaryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, C(═O)NH 2 , PO(OH) 2  and S(O) 2 OH; and    X is (CH 2 ) m , wherein m is 1 or 2.    
     
     
         17 . An MRI contrast agent according to  claim 16 , wherein: 
 A is CR 3  or N;    R 3  is selected from the group consisting of H, C 1 -C 10  alkyl and C 1 -C 10  aryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, PO(OH) 2  and S(O) 2 OH; and    X is selected from: (CH 2 ) m , wherein m is 1 or 2.    
     
     
         18 . An MRI contrast agent according to  claim 17 , wherein said tripodal polyaminophosphonate chelant has the formula:  
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of phenyl, benzyl, imidazolyl, pyridyl and thiophenyl, each substituted with 0-2 OH.  
       
     
     
         19 . An MRI contrast agent according to  claim 18 , wherein said tripodal polyaminophosphonate chelant has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         20 . An X-ray or CT contrast agent comprising a tripodal polyaminophosphonate chelant according to  claim 1 , chelated with a heavy metal ion of atomic number 21-31, 39-50, 56-80, 82, 83 or 90.  
     
     
         21 . An X-ray or CT contrast agent according to  claim 20 , wherein: 
 A is selected from the group consisting of CR 3 , N and P═O;    R 1  is (CH 2 ) n R 6 ,    R 3  and R 6  are independently selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7 , fluoroaryl substituted with 0-2 R 7  and heteroaryl substituted with 0-2 R 7 ;    X is selected from the group consisting of (CR 9 R 10 ) m , NR 11 , and O(CR 9 R 10 ) m , wherein m is an integer selected from 1 to 3, provided that when A is N, X is (CR 9 R 10 ) m ;    R 11  is selected from the group consisting of H, C 1 -C 10  alkyl substituted with 0-2 R 7 , C 1 -C 10  fluoroalkyl substituted with 0-2 R 7 , C 2 -C 10  alkenyl substituted with 0-2 R 7 , C 2 -C 10  fluoroalkenyl substituted with 0-2 R 7 , aryl substituted with 0-2 R 7  and fluoroaryl substituted with 0-2 R 7 .    
     
     
         22 . An X-ray or CT contrast agent according to  claim 21 , wherein: 
 A is CR 3  or N;    n is 0 or 1;    R 3  is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  fluoroalkyl, C 2 -C 10  alkenyl, C 2 -C 10  fluoroalkenyl, aryl and fluroaryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, C(═O)NH 2 , PO(OH) 2  and S(O) 2 OH; and    X is (CH 2 ) m , wherein m is 1 or 2.    
     
     
         23 . An X-ray or CT contrast agent according to  claim 22 , wherein: 
 A is CR 3  or N;    R 3  is selected from the group consisting of H, C 1 -C 10  alkyl and C 1 -C 10  aryl;    R 6  is an aryl or heteroaryl group substituted with 0-2 R 7 ;    R 7  is selected from the group consisting of H, OH, C(═O)OH, PO(OH) 2  and S(O) 2 OH; and    X is selected from: (CH 2 ) m , wherein m is 1 or 2.    
     
     
         24 . An X-ray or CT contrast agent according to  claim 23 , wherein said tripodal polyaminophosphonate chelant has the formula:  
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of phenyl, benzyl, imidazolyl, pyridyl and thiophenyl, each substituted with 0-2 OH.  
       
     
     
         25 . An X-ray or CT contrast agent according to  claim 24 , wherein said tripodal polyaminophosphonate chelant has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         26 . A radiopharmaceutical composition for treating bone disorders that benefit from the delivery of cytotoxic doses of radiation to the bone tissues of a patient in need thereof, comprising a therapeutically effective amount of the tripodal poly-aminophosphonate chelant of  claim 7  and a pharmaceutically acceptable carrier.  
     
     
         27 . A method for treating bone disorders that benefit from the delivery of cytotoxic doses of radiation to the bone tissues of a patient in need thereof, comprising administering to said patient an effective amount of the radiopharmaceutical composition of  claim 26 .  
     
     
         28 . The method of  claim 27 , wherein said method comprises relieving bone pain, suppressing bone marrow or treating bone cancer.  
     
     
         29 . The method of  claim 28 , wherein said method comprises treating bone cancer.  
     
     
         30 . The method of  claim 29 , wherein the bone cancer comprises a primary tumor.  
     
     
         31 . The method of  claim 29 , wherein the bone cancer tumor comprises a secondary tumor.  
     
     
         32 . A composition for radioactive imaging comprising an effective amount of the radiopharmaceutical compound of  claim 8  and a pharmaceutically acceptable carrier, wherein the radio-nuclide is selected from the group consisting of  52m Mn,  52 Fe,  55 Co,  64 Cu,  60 Cu,  62 Cu,  67 Ga,  68 Ga,  94m Tc,  99m Tc, and  111 In.  
     
     
         33 . A method for radioactive imaging comprising administering to a patient to be imaged sufficiently in advance thereto an effective amount of the radioactive imaging composition of  claim 32 .  
     
     
         34 . A method according to  claim 33 , wherein said method is for imaging bone metastases, bone disorders, myocardial infarction, infarctions of the spleen and bowel, inflammatory bowel disease, radiation injury and metastastic calcification.  
     
     
         35 . A method according to  claim 33 , wherein said imaging method is gamma scintigraphy or positron-emission tomography.  
     
     
         36 . A composition for X-ray imaging comprising an effective amount of the contrast agent of  claim 20  and a pharmaceutically acceptable carrier.  
     
     
         37 . A method for X-ray imaging comprising administering to a patient to be imaged sufficiently in advance thereof an effective amount of the X-ray imaging composition of  claim 36 .  
     
     
         38 . A method according to  claim 37 , wherein said method is for imaging bone metastases, bone disorders, myocardial infarction, infarctions of the spleen and bowel, inflammatory bowel disease, radiation injury and metastastic calcification.  
     
     
         39 . A method according to  claim 37 , wherein said X-ray imaging method is CT imaging.  
     
     
         40 . A composition for magnetic resonance imaging comprising an effective amount of the contrast agent of  claim 14  and a pharmaceutically acceptable carrier.  
     
     
         41 . A method for magnetic resonance imaging comprising administering to a patient to be imaged sufficiently in advance thereof an effective amount of the magnetic resonance imaging composition of  claim 40 .  
     
     
         42 . A method according to  claim 41 , wherein said method is for imaging bone metastases, bone disorders, myocardial infarction, infarctions of the spleen and bowel, inflammatory bowel disease, radiation injury and metastastic calcification.  
     
     
         43 . A pharmaceutical composition for treating heavy metal toxicity in a patient in need thereof, comprising a therapeutically effective amount of the tripodal polyaminophosphonate chelant of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         44 . A method for treating heavy metal toxicity in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 43 .  
     
     
         45 . A radiopharmaceutical treatment kit comprising: a sterile, non-pyrogenic formulation comprising a radiopharmaceutical composition according to  claim 26 , a pH 3-9 buffering agent and optionally one or more additives selected from the group consisting of ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids, bacteriostats and equipment for administering said composition.  
     
     
         46 . The treatment kit of  claim 45 , wherein said formulation is in the form of a sterile solution or lyophilized solid.  
     
     
         47 . A diagnostic kit comprising: a sterile, non-pyrogenic formulation comprising a radiopharmaceutical composition according to  claim 32 , a pH 3-9 buffering agent and optionally one or more additives selected from the group consisting of ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids, bacteriostats and equipment for administering said composition.  
     
     
         48 . The diagnostic kit of  claim 47 , wherein said formulation is in the form of a sterile solution or lyophilized solid.  
     
     
         49 . A diagnostic kit comprising: a sterile, non-pyrogenic formulation comprising an X-ray imaging composition according to  claim 36 , a pH 3-9 buffering agent and option-ally one or more additives selected from the group consisting of ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids, bacteriostats and equipment for administering said composition.  
     
     
         50 . The diagnostic kit of  claim 49 , wherein said formulation is in the form of a sterile solution or lyophilized solid.  
     
     
         51 . A diagnostic kit comprising: a sterile, non-pyrogenic formulation comprising a magnetic resonance imaging composition according to  claim 40 , a pH 3-9 buffering agent and optionally one or more additives selected from the group consisting of ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids, bacteriostats and equipment for administering said composition.  
     
     
         52 . The diagnostic kit of  claim 51 , wherein said formulation is in the form of a sterile solution or lyophilized solid.  
     
     
         53 . A radiopharmaceutical composition for treating bone disorders that benefit from the delivery of cytotoxic doses of radiation to the bone tissues of a patient in need thereof, comprising a therapeutically effective amount of the radiopharmaceutical compound of  claim 8  and a pharmaceutically acceptable carrier.  
     
     
         54 . A method for treating bone disorders that benefit from the delivery of cytotoxic doses of radiation to the bone tissues of a patient in need thereof, comprising administering to said patient an effective amount of the radiopharmaceutical composition of  claim 53 .  
     
     
         55 . The method of  claim 54 , wherein said method comprises relieving bone pain, suppressing bone marrow or treating bone cancer.  
     
     
         56 . The method of  claim 55 , wherein said method comprises treating bone cancer.  
     
     
         57 . The method of  claim 56 , wherein the bone cancer comprises a primary tumor.  
     
     
         58 . The method of  claim 56 , wherein the bone cancer tumor comprises a secondary tumor.  
     
     
         59 . A radiopharmaceutical treatment kit comprising: a sterile, non-pyrogenic formulation comprising a radiopharmaceutical composition according to  claim 53 , a pH 3-9 buffering agent and optionally one or more additives selected from the group consisting of ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabiliza-tion aids, solubilization aids, bacteriostats and equipment for administering said composition.  
     
     
         60 . The treatment kit of  claim 59 , wherein said formulation is in the form of a sterile solution or lyophilized solid.