Radiosynthesis of Tau Radiopharmaceuticals

Abstract

This disclosure relates to a one-step method for preparing the tau radiopharmaceutical, [18F]T807, using an unprotected or protected precursor (e.g., tertbutyl 7-(6-nitropyridin-3-yl)-SH-pyrido[4,3-b]indole-5-carboxylate). An improved one-step synthesis method to prepare [18F]T807 was achieved with a protected (e.g., t-BOC) precursor, offering increased solubility, a faster synthesis as well as simpler purification and automation. [18F]T807 was validated for human use with a GE TRACERlab™ FXFN radiosynthesis module. The methodology demonstrated herein should facilitate multi-center trials and widespread use for tauopathy imaging with this radiopharmaceutical.

1 . A process for preparing a compound of formula (II): 
       
         
           
           
               
               
           
         
         the method comprising: 
         reacting a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is H or a protecting group; and 
         Z is a leaving group, 
         with a radiofluorinating agent to prepare the compound of formula (II). 
       
     
     
         2 . The process of  claim 1 , wherein X is a carbamate protecting group. 
     
     
         3 . (canceled) 
     
     
         4 . The process of  claim 1 , wherein Z is selected from the group consisting of: triflate, mesylate, nonaflate, hexaflate, tosylate, nosylate, brosylate, perfluoroalkyl sulfonate, tetraphenylborate, hexafluorophosphate, trifluoroacetate, tetrafluoroborate, perchlorate, perfluoroalkylcarboxylate, nitro, azide, chloride, bromide, or iodide. 
     
     
         5 . (canceled) 
     
     
         6 . The process of  claim 1 , wherein the radio fluorinating agent is potassium cryptand [ 18 F]fluoride (K[ 18 F]/K 222 ). 
     
     
         7 . The process of  claim 1 , wherein the process is performed at a temperature ranging from about 60 to about 200° C. 
     
     
         8 . (canceled) 
     
     
         9 . The process of  claim 7 , wherein the heating occurs for a time period ranging from about 1 minutes to about 30 minutes. 
     
     
         10 .- 13 . (canceled) 
     
     
         14 . The process of  claim 1 , wherein the compound of formula (II) is formulated with a carrier. 
     
     
         15 . The process of  claim 1 , wherein the carrier is sodium chloride for injection. 
     
     
         16 . (canceled) 
     
     
         17 . The process of  claim 1 , wherein the process is performed in an automated radiosynthesis module. 
     
     
         18 . A process for preparing a compound of formula (II): 
       
         
           
           
               
               
           
         
         the method comprising: 
         reacting a compound: 
       
       
         
           
           
               
               
           
         
         with a potassium cryptand [ 18 F]fluoride (K[ 18 F]/K 222 ) in DMSO at 130° C. to prepare the compound of formula (II). 
       
     
     
         19 . The process of  claim 18 , wherein the reacting occurs for a time period ranging from about 1 minutes to about 30 minutes. 
     
     
         20 .- 22 . (canceled) 
     
     
         23 . The process of  claim 18 , wherein the compound of formula (II) is formulated with a pharmaceutically acceptable carrier. 
     
     
         24 . The process of  claim 18 , wherein the carrier is sodium chloride for injection. 
     
     
         25 . The process of  claim 24 , wherein the sodium chloride is 0.9% sodium chloride. 
     
     
         26 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         prepared by a process comprising: 
         reacting a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein X is H or a protecting group, 
         with a radiofluorinating agent to prepare the compound of formula (II). 
       
     
     
         27 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein X is a protecting group; and 
         Z is a leaving group. 
       
     
     
         28 . The compound of  claim 27 , wherein X is a carbamate protecting group. 
     
     
         29 . (canceled) 
     
     
         30 . The compound of  claim 27 , wherein Z is selected from the group consisting of triflate, mesylate, nonaflate, hexaflate, tosylate, nosylate, brosylate, perfluoroalkyl sulfonate, tetraphenylborate, hexafluorophosphate, trifluoroacetate, tetrafluoroborate, perchlorate, perfluoroalkylcarboxylate, nitro, azide, chloride, bromide, or iodide. 
     
     
         31 . (canceled) 
     
     
         32 . The compound of  claim 27 , wherein the compound of formula (I) is: