Methods and kits for preparing radionuclide complexes

Abstract

A method for preparing a complex comprising a radioisotope of gallium for use in radiotherapy or in a medical imaging procedure, said method comprising adding a gallium radioisotope solution obtained directly from a gallium radionuclide generator to a composition comprising a pharmaceutically acceptable buffer and optionally also a pharmaceutically acceptable basic reagent, in amounts sufficient to increase the pH to a level in the range of 3 to 8, wherein the composition further comprises a chelator that is able to chelate radioactive gallium within said pH range and at moderate temperature, said chelator being optionally linked to a biological targeting agent.

1 . A method for preparing a complex comprising a radioisotope of gallium for use in radiotherapy or in a medical imaging procedure, said method comprising adding a gallium radioisotope solution obtained directly from a gallium radionuclide generator to a composition comprising a pharmaceutically acceptable buffer and optionally also a pharmaceutically acceptable basic reagent, in amounts sufficient to increase the pH to a level in the range of 3 to 8, wherein the composition further comprises a chelator that is able to chelate radioactive gallium within said pH range and at moderate temperature, said chelator being optionally linked to a biological targeting agent. 
     
     
         2 . The method of  claim 1  wherein the gallium solution is an eluate obtained directly from a gallium-68 radionuclide generator. 
     
     
         3 . The method of  claim 2  wherein the eluate is at a pH of less than 2. 
     
     
         4 . The method of  claim 1  wherein the composition comprises the pharmaceutically acceptable basic reagent, the pharmaceutically acceptable basic reagent is chosen from an alkali metal hydroxide, carbonate or bicarbonate, and the alkali metal is sodium or potassium. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1  wherein the chelator is linked to the biological targeting agent. 
     
     
         7 . The method of  claim 1  wherein the chelator is a compound of formula (I) 
       
         
           
           
               
               
           
         
         or a salt thereof; wherein one of X and Y is C=0 and the other is NR; wherein each m and p are independently selected from 0 to 6; wherein R 1  is a chelating group capable of chelating a radionuclide and is selected from: 
       
       
         
           
           
               
               
           
         
         wherein R, R 2 , R 3  and R 4  are independently hydrogen or an optionally substituted C 1-7 alkyl group; 
         and where Z is hydrogen or a group of formula -B′-H, -B′-A, or a group -B′-A*-T, where 
         T is a targeting group capable of binding to a target of interest in a subject; 
         A is a reactive group allowing coupling to the group T, 
         A* is a reacted reactive group A; 
         B′ is a linker group for linking the chelating group to a reactive group A, and is represented by the formula: 
       
       
         
           
           
               
               
           
         
         wherein each Q is independently selected from a group consisting of —NR 5 —, —C(O)NR 5 —, —C(O)O, —NR 5 C(O)NR 5 —, —NR 5 C(S)NR 5 — and —O—, each R 5  is independently hydrogen or an optionally substituted C 1-7  alkyl group, each q and s are independently selected from 0 to 6 and each r is independently selected from 1 to 6. 
       
     
     
         8 - 10 . (canceled) 
     
     
         11 . The method of  claim 1  wherein the pharmaceutically acceptable buffer is a phosphate buffer, bicarbonate or carbonate buffer, succinate buffer, borate buffer, cacodylate buffer, citrate buffer, sodium chloride, zinc chloride, a zwitterionic buffer, a tris(hydroxymethyl)aminomethane (TRIS) buffer, morpholine propanesulphonic acid (MOPS), N-(2-hydroxyethyl) piperazine-N′(2-ethanesulfonic acid) (HEPES), dextrose, lactose, tartaric acid, arginine or an acetate buffer. 
     
     
         12 . The method of  claim 1  wherein the chelator comprises the biological targeting agent the biological targeting agent is a ligand that targets a cancer specific marker, and the cancer specific marker is prostate specific membrane antigen (PSMA). 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1  wherein the gallium radioisotope solution is obtained by eluting a  68 Ga radionuclide column with an inorganic acid. 
     
     
         15 . (canceled) 
     
     
         16 . A kit for use in the method of  claim 1 , said kit comprising a composition comprising a pharmaceutically acceptable buffer, a chelator that is able to chelate radioactive gallium within a pH range of from 3 to 8 and at moderate temperature, said chelator being optionally linked to a biological targeting agent and optionally also a pharmaceutically acceptable basic reagent, wherein the composition produces a solution having a pH in the range of from 3 to 8 when a solution obtained directly from a gallium radionuclide generator is added thereto. 
     
     
         17 . The kit of  claim 16  wherein the composition is in liquid form. 
     
     
         18 . The kit of  claim 16  wherein components of the kit are in lyophilized or freeze-dried form. 
     
     
         19 . (canceled) 
     
     
         20 . The kit of  claim 16  wherein the chelator is a compound of formula (I) 
       
         
           
           
               
               
           
         
         or a salt thereof; wherein one of X and Y is C=0 and the other is NR; wherein each m and p are independently selected from 0 to 6; wherein R 1  is a chelating group capable of chelating a radionuclide and is selected from: 
       
       
         
           
           
               
               
           
         
         wherein R, R 2 , R 3  and R 4  are independently hydrogen or an optionally substituted C 1-7 alkyl group; 
         and where Z is hydrogen or a group of formula -B′-H, -B′-A, or a group -B′-A*-T, where 
         T is a targeting group capable of binding to a target of interest in a subject; 
         A is a reactive group allowing coupling to the group T, 
         A* is a reacted reactive group A; 
         B′ is a linker group for linking the chelating group to a reactive group A, and is represented by the formula: 
       
       
         
           
           
               
               
           
         
         wherein each Q is independently selected from a group consisting of —NR 5 —, —C(O)NR 5 —, —C(O)O, —NR 5 C(O)NR 5 —, —NR 5 C(S)NR 5 — and —O—, each R 5  is independently hydrogen or an optionally substituted C 1-7  alkyl group, each q and s are independently selected from 0 to 6 and each r is independently selected from 1 to 6. 
       
     
     
         21 . A unitary composition for use in the method of  claim 1 , said composition comprising (i) a chelator which is able to chelate with a gallium radionuclide at pH 3 to 8 and at moderate temperature, optionally linked to a biological targeting agent, (ii) a pharmaceutically acceptable buffer and optionally also (iii) a pharmaceutically acceptable basic reagent, wherein (ii) and (iii) are present in the composition in amounts sufficient to result in a pH in the range of from 3 to 8 when a solution obtained directly from a gallium radionuclide generator is added thereto. 
     
     
         22 . The composition of  claim 21  wherein the gallium radionuclide chelator is a compound of formula (I) 
       
         
           
           
               
               
           
         
         or a salt thereof; wherein one of X and Y is C=0 and the other is NR; wherein each m and p are independently selected from 0 to 6; wherein R 1  is a chelating group capable of chelating a radionuclide and is selected from: 
       
       
         
           
           
               
               
           
         
         wherein R, R 2 , R 3  and R 4  are independently hydrogen or an optionally substituted C 1-7 alkyl group; 
         and where Z is hydrogen or a group of formula -B′-H, -B′-A, or a group -B′-A*-T, where 
         T is a targeting group capable of binding to a target of interest in a subject; 
         A is a reactive group allowing coupling to the group T, 
         A* is a reacted reactive group A; 
         B′ is a linker group for linking the chelating group to a reactive group A, and is represented by the formula: 
       
       
         
           
           
               
               
           
         
         wherein each Q is independently selected from a group consisting of —NR 5 —, —C(O)NR 5 —, —C(O)O, —NR 5 C(O)NR 5 —, —NR 5 C(S)NR 5 — and —O—, each R 5  is independently hydrogen or an optionally substituted C 1-7  alkyl group, each q and s are independently selected from 0 to 6 and each r is independently selected from 1 to 6. 
       
     
     
         23 . The composition of  claim 21  which is lyophilized or freeze-dried form. 
     
     
         24 . The composition of  claim 21  which, in solution, has pH the range of from 3.0 to 8. 
     
     
         25 . The composition of  claim 21  which includes the pharmaceutically acceptable basic reagent, the pharmaceutically acceptable basic reagent is chosen from an alkali metal hydroxide, carbonate or bicarbonate, and the alkali metal is sodium or potassium. 
     
     
         26 . (canceled) 
     
     
         27 . The composition of  claim 21  wherein the pharmaceutically acceptable buffer is a phosphate buffer, bicarbonate or carbonate buffer, succinate buffer, borate buffer, cacodylate buffer, citrate buffer, sodium chloride, zinc chloride, a zwitterionic buffer, a tris(hydroxymethyl)aminomethane (TRIS) buffer, morpholine propanesulphonic acid (MOPS), N-(2-hydroxyethyl) piperazine-N′(2-ethanesulfonic acid) (HEPES), dextrose, lactose, tartaric acid, arginine or an acetate buffer. 
     
     
         28 . The composition of  claim 21  wherein the biological targeting agent is a ligand that targets a cancer specific marker, and the cancer specific marker is prostate specific membrane antigen (PSMA). 
     
     
         29 . (canceled) 
     
     
         30 . The composition of  claim 21  which further comprises a free-radical scavenger. 
     
     
         31 - 34 . (canceled)