Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor

Abstract

Disclosed is a method for producing a fluorine-18-labeled, translocator protein overexpression-targeting PET radiotracer including: preparing a fluorine-18 reaction solution; producing a ((4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (aryl)iodonium) anion precursor as an iodonium salt precursor; producing a 2-(6,8-dichloro-2-(4-(4,4,5,6-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazo[1,2-a]pyridin-3-yl-N,N-dipropylacetamide precursor as a boron ester precursor; producing an iodonium salt precursor reaction solution; preparing a boron ester precursor reaction solution; and producing a radiotracer composition containing a fluorine-18-labeled radiotracer by reacting the iodonium salt or boron ester precursor reaction solution with the fluorine-18-labeled reaction solution. The use of the fluorine-18-labeled PET radiotracer makes it possible to diagnose patients with various brain diseases and tumors by obtaining new images of neuroinflammation, stroke and tumors associated with translocator protein overexpression through PET. In addition, by virtue of the long half-life of fluorine 18, the PET radiotracer can provide brain neuroinflammation and tumor imaging diagnostics to a larger number of patients compared to conventional carbon-11 tracers.

What is claimed is: 
     
         1 . A method for producing a fluorine-18-labeled positron emission tomography (PET) radiotracer for targeting translocator protein overexpression, the method comprising the steps of:
 preparing a solvent-evaporated fluorine-18 reaction solution by adding water having fluorine-18 dissolved therein to acetonitrile, followed by heating to a temperature of 85 to 95° C.;   producing an iodonium salt precursor by reacting a 2-aryl-6,8-dichloroimidazopyridine derivative with a (diacetoxy)iodoarene derivative;   preparing an iodonium salt precursor reaction solution by dissolving the iodonium salt precursor and 2,2,6,6-tetramethyl-1-piperidinyloxyl in acetonitrile; and   producing a radiotracer composition containing a fluorine-18-labeled radiotracer compound by adding the iodonium salt precursor reaction solution to the fluorine-18 reaction solution, followed by heating and reaction.   
     
     
         2 . The method of  claim 1 , further comprising a first purification step of purifying the radiotracer composition by adding an aqueous hydrochloric acid solution to the radiotracer composition, followed by adsorption onto a C18 Sep-Pak cartridge, washing with water, and then elution with ethanol. 
     
     
         3 . The method of  claim 1 , further comprising a second purification step of purifying the composition using a high-performance liquid chromatography (HPLC) system equipped with a 244 to 264 nm UV detector and a radioisotope gamma-ray detector. 
     
     
         4 . The method of  claim 1 , wherein the step of preparing the fluorine-18 reaction solution is performed by further adding cesium hydrogen carbonate (CsHCO3) and 18-crown-6 ([C 2 H 4 O] 6 ) to the acetonitrile. 
     
     
         5 . A method for producing a fluorine-18-labeled positron emission tomography (PET) radiotracer for targeting translocator protein overexpression, the method comprising the steps of:
 preparing a solvent-evaporated fluorine-18 reaction solution by adding water having fluorine-18 dissolved therein to acetonitrile, followed by heating to a temperature of 85 to 95° C.;   producing a boron ester precursor by reacting a 2-aryl-6,8-dichloroimidazopyridine derivative with bis(pinacolato)diboron;   preparing a boron ester precursor reaction solution by dissolving the boron ester precursor and a copper catalyst (copper(II) trifluoromethanesulfonate, or tetrakis(pyridine)copper(II) triflate) in dimethylformamide (DMF); and   producing a radiotracer composition containing a fluorine-18-labeled radiotracer compound by adding the boron ester precursor reaction solution to the fluorine-18 reaction solution, followed by heating and reaction.   
     
     
         6 . The method of  claim 5 , further comprising a first purification step of purifying the radiotracer composition by adding an aqueous hydrochloric acid solution to the radiotracer composition, followed by adsorption onto a C18 Sep-Pak cartridge, washing with water, and then elution with ethanol. 
     
     
         7 . The method of  claim 5 , further comprising a second purification step of purifying the composition using a high-performance liquid chromatography (HPLC) system equipped with a 244 to 264 nm UV detector and a radioisotope gamma-ray detector. 
     
     
         8 . The method of  claim 5 , wherein the step of preparing the fluorine-18 reaction solution is performed by further adding cesium hydrogen carbonate (CsHCO 3 ) and 18-crown-6 ([C 2 H 4 O] 6 ) to the acetonitrile. 
     
     
         9 . A fluorine-18-labeled positron emission tomography (PET) radiotracer for targeting translocator protein overexpression, which is represented by Formula 1 below and produced by a method comprising the steps of:
 preparing a solvent-evaporated fluorine-18 reaction solution by adding water having fluorine-18 dissolved therein to acetonitrile, followed by heating to a temperature of 85 to 95° C.;   producing an iodonium salt precursor by reacting a 2-aryl-6,8-dichloroimidazopyridine derivative with a (diacetoxy)iodoarene derivative;   preparing an iodonium salt precursor reaction solution by dissolving the iodonium salt precursor and 2,2,6,6-tetramethyl-1-piperidinyloxyl in acetonitrile; and   producing a radiotracer composition containing a fluorine-18-labeled radiotracer compound by adding the iodonium salt precursor reaction solution to the fluorine-18 reaction solution, followed by heating and reaction:   
       
         
           
           
               
               
           
         
         wherein R is  18 F or  19 F, X is C or N, and Y is C or N. 
       
     
     
         10 . A precursor for synthesizing the fluorine-18-labeled positron emission tomography (PET) radiotracer for targeting translocator protein overexpression of  claim 9 , wherein a 2-fluoroaryl-6,8-dichloroimidazopyridine derivative of Formula 1 is a 2-aryl-6,8-dichloroimidazopyridine derivative represented by Formula 2 below: 
       
         
           
           
               
               
           
         
       
       wherein X is C or N, and Y is C or N. 
     
     
         11 . The precursor of  claim 10 , wherein Z in Formula 2 is a functional group selected from the group consisting of iodobenzene tosylate, iodotoluene tosylate, 2-iodo-1,3,5-trimethylbenzene tosylate, 4-iodoanisole tosylate, 3-iodoanisole tosylate, 2-iodothiophene tosylate, 3-iodothiophene tosylate, iodobenzene bromide, iodotoluene bromide, 2-iodo-1,3,5-trimethylbenzene bromide, 4-iodoanizole bromide, 3-iodoanisole bromide, 2-iodocyophene bromide, 3-iodothiophene bromide, iodobenzene iodide, iodotoluene iodide, 2-iodo-1,3,5-trimethylbenzene iodide, 4-iodoanisole iodide, 3-iodoanisole iodide, 2-iodothiophene iodide, 3-iodothiophene iodide, iodobenzene triflate, iodotoluene triflate, 2-iodo-1,3,5-trimethylbenzene triflate, 4-iodoanisole triflate, 3-iodoanisole triflate, 2-iodothiophene triflate, 3-iodothiophene triflate, and pinacol boron ester. 
     
     
         12 . A fluorine-18-labeled positron emission tomography (PET) radiotracer for targeting translocator protein overexpression, which is represented by Formula 1 below and produced by a method comprising the steps of:
 preparing a solvent-evaporated fluorine-18 reaction solution by adding water having fluorine-18 dissolved therein to acetonitrile, followed by heating to a temperature of 85 to 95° C.;   producing a boron ester precursor by reacting a 2-aryl-6,8-dichloroimidazopyridine derivative with bis(pinacolato)diboron;   preparing a boron ester precursor reaction solution by dissolving the boron ester precursor and a copper catalyst (copper(II) trifluoromethanesulfonate, or tetrakis(pyridine)copper(II) triflate) in dimethylformamide (DMF); and   producing a radiotracer composition containing a fluorine-18-labeled radiotracer compound by adding the boron ester precursor reaction solution to the fluorine-18 reaction solution, followed by heating and reaction:   
       
         
           
           
               
               
           
         
         wherein R is  18 F or  19 F, X is C or N, and Y is C or N. 
       
     
     
         13 . A precursor for synthesizing the fluorine-18-labeled positron emission tomography (PET) radiotracer for targeting translocator protein overexpression of  claim 12 , wherein a 2-fluoroaryl-6,8-dichloroimidazopyridine derivative of Formula 1 is a 2-aryl-6,8-dichloroimidazopyridine derivative represented by Formula 2 below: 
       
         
           
           
               
               
           
         
       
       wherein X is C or N, and Y is C or N. 
     
     
         14 . The precursor of  claim 13 , wherein Z in Formula 2 is a functional group selected from the group consisting of iodobenzene tosylate, iodotoluene tosylate, 2-iodo-1,3,5-trimethylbenzene tosylate, 4-iodoanisole tosylate, 3-iodoanisole tosylate, 2-iodothiophene tosylate, 3-iodothiophene tosylate, iodobenzene bromide, iodotoluene bromide, 2-iodo-1,3,5-trimethylbenzene bromide, 4-iodoanizole bromide, 3-iodoanisole bromide, 2-iodocyophene bromide, 3-iodothiophene bromide, iodobenzene iodide, iodotoluene iodide, 2-iodo-1,3,5-trimethylbenzene iodide, 4-iodoanisole iodide, 3-iodoanisole iodide, 2-iodothiophene iodide, 3-iodothiophene iodide, iodobenzene triflate, iodotoluene triflate, 2-iodo-1,3,5-trimethylbenzene triflate, 4-iodoanisole triflate, 3-iodoanisole triflate, 2-iodothiophene triflate, 3-iodothiophene triflate, and pinacol boron ester. 
     
     
         15 . A fluorescent dye-labeled or sensitizer-labeled, translocator protein overexpression-targeting ligand tracer for fluorescence imaging-guided surgery and photodynamic therapy, which is represented by Formula 3 below and produced by a method comprising the step of producing a sensitizer-labeled ligand as a fluorescent ligand by reacting a precursor of a 2-aryl-6,8-dichloroimidazopyridine derivative with a fluorescent dye or a photodynamic therapy sensitizer, which has a functional group for complementary bonding to the precursor: 
       
         
           
           
               
               
           
         
         wherein X is C or N; Y is C or N; the number (n) of polyethylene glycol (PEG) chains is 1 to 10; the linker that connects the PEG to the fluorescent dye or the photodynamic therapy sensitizer is a compound selected from the group consisting of ether, amide, ester, urea, urethane, thiourea, and disulfide; and the PEG is substituted at any one of the 2-, 3- or 4-positions of the ring containing X and Y. 
       
     
     
         16 . The fluorescent dye-labeled or sensitizer-labeled, translocator protein overexpression-targeting ligand tracer of  claim 15 , wherein the linker is a linker selected from the group consisting of ether, amide, ester, urea, urethane, thiourea, and disulfide. 
     
     
         17 . The fluorescent dye-labeled or sensitizer-labeled, translocator protein overexpression-targeting ligand tracer of  claim 15 , wherein the PEG chain-substituted 2-aryl-6,8-dichloroimidazopyridine derivative having a fluorescent dye or sensitizer introduced thereto as represented by Formula 3 above is synthesized from a PEG chain-substituted 2-aryl-6,8-dichloroimidazopyridine derivative precursor of Formula 4 below: 
       
         
           
           
               
               
           
         
         wherein X is C or N; Y is C or N, the number (n) of the polyethylene glycol (PEG) chains is 1 to 10, and the PEG is substituted at any one of the 2-, 3- and 4-position of the ring containing X and Y. 
       
     
     
         18 . The fluorescent dye-labeled or sensitizer-labeled, translocator protein overexpression-targeting ligand tracer of  claim 15 , wherein Z in Formula 4 is a functional group selected from the group consisting of acid, alcohol, thiol, amine, isocyanate, isothiocyanate, bromide, iodide, chloride, N-succinimidyl ester, and sulfo-N-succinimidyl ester.