Mono-, di- or polysaccharide used as metal inhibitor in the preparation of 68ga-chelate-functionalized targeting agent

Abstract

The present invention relates the use of metal inhibitor in radiolabelling reactions using radioactive metals.

1 - 39 . (canceled) 
     
     
         40 . A method for radiolabelling a chelate-functionalized targeting agent for use in in-vivo PET imaging with a metal radionuclide, comprising the steps of:
 a) providing a chelate-functionalized targeting agent, able to chelate the metal radionuclide in a radiolabelling reaction, wherein the chelate functional group of the chelate-functionalized targeting agent is selected from the group consisting of DOTA, NOTA, NODAGA, HBED, DFO, EDTA, 6SS, B6SS, PLED, TAME, YM103 and H 2 dedpa;   b) adding a metal inhibitor not chemically linked to said chelate-functionalized targeting agent, to the radiolabelling reaction obtained in a), said metal inhibitor being a co-chelating agent selected from the group consisting of: beta-cyclodextrin, a disaccharide and a monosaccharide, capable of inactivating metals other than metal radionuclides without interfering with the chelation between the metal radionuclide and the chelate-functionalized targeting agent, under the conditions of the radiolabelling reaction, thereby obtaining a mixture of the chelate-functionalized targeting agent of a) and the metal inhibitor of b) which are not chemically linked to each other when present in said mixture; and   c) adding a metal radionuclide that is an isotope of a metal selected from the group consisting of copper, gallium, lutetium, indium, scandium, and zirconium to the mixture of a) and b) in an acetate buffer allowing to maintain the pH in the range 3-7;   wherein the targeting agent of said chelate-functionalized targeting agent is selected from the group consisting of a peptide, a peptide comprising 2 to 20 amino acids, a polypeptide, an antibody, a nanobody, a diabody, an antibody fragment, a nucleic acid, an aptamer, an antisense oligonucleotide, and an organic molecule.   
     
     
         41 . The method according to  claim 40 , wherein said metal inhibitor is present in micromolar amounts. 
     
     
         42 . The method according to  claim 40 , wherein the radiolabelling reaction is carried out at a temperature of below 50° C. 
     
     
         43 . The method according to  claim 40 , wherein the radiolabelling reaction is performed at a pH between 3 and 7. 
     
     
         44 . The method according to  claim 40 , wherein the metal radionuclide is selected from the group consisting of copper-64, gallium-68, gallium-67, gallium-66, lutetium-177, indium-114, indium-111, scandium-47, scandium-44, scandium-43, and zirconium-89. 
     
     
         45 . The method according to  claim 40 , wherein the monosaccharide is selected from the group consisting of: Glucose, Fructose, and D-Mannose. 
     
     
         46 . A kit for radiolabelling of a chelate-functionalized targeting agent for use in in-vivo PET imaging comprising:
 a chelate-functionalized targeting agent, able to chelate a metal radionuclide in a radiolabelling reaction, wherein the chelate-functional group of the chelate-functionalized targeting agent is selected from the group consisting of DOTA, NOTA, NODAGA, HBED, DFO, EDTA, 6SS, B6SS, PLED, TAME, YM103 and H 2 dedpa;   a metal inhibitor, which is not chemically linked to said chelate-functionalized targeting agent and which is a co-chelating agent selected from the group consisting of beta-cyclodextrin, a disaccharide and a monosaccharide, capable of inactivating metals other than metal radionuclides without interfering with the chelation between the metal radionuclide and the chelate-functionalized targeting agent, under the conditions of the radiolabelling reaction;   a metal radionuclide that is an isotope of a metal selected from the group consisting of copper, gallium, lutetium, indium, scandium, and zirconium; and   an acetate buffer, allowing to maintain the pH in the range 3-7,   wherein the targeting agent of said chelate-functionalized targeting agent is selected from the group consisting of a peptide, a peptide comprising 2 to 20 amino acids, a polypeptide, an antibody, a nanobody, a diabody, an antibody fragment, a nucleic acid, an aptamer, an antisense oligonucleotide, and an organic molecule.   
     
     
         47 . The kit according to  claim 46 , wherein said metal inhibitor is present in micromolar amounts. 
     
     
         48 . The kit according to  claim 46 , wherein the metal radionuclide is selected from the group consisting of copper-64, gallium-68, gallium-67, gallium-66, lutetium-177, indium-114, indium-111, scandium-47, scandium-44, scandium-43, and zirconium-89. 
     
     
         49 . The kit according to  claim 46 , wherein the monosaccharide is selected from the group consisting of Glucose, Fructose, and D-Mannose. 
     
     
         50 . The kit according to  claim 46 , wherein said chelate-functionalized targeting agent and metal inhibitor are lyophilised. 
     
     
         51 . An in vivo method for imaging a subject comprising the steps of:
 1) producing a radiolabelled chelate-functionalized targeting agent using the method of  claim 40 ;   2) administering said radiolabelled chelate-functionalized targeting agent to the subject; and   3) detecting said radiolabelled chelate-functionalized targeting agent in the subject using positron emission tomography (PET).