18f-fluciclovine compositions in citrate buffers

Abstract

The present invention provides a pharmaceutical composition comprising [ 18 F]FACBC having certain advantages over known compositions comprising [ 18 F]FACBC. Also provided by the present invention is a method to obtain the composition of the invention.

1 - 21 . (canceled) 
     
     
         22 . A positron emission tomography (PET) tracer composition comprising anti-1-amino-3- 18 F-fluorocyclobutyl-1-carboxylic acid ( 18 F-FACBC) having an end of synthesis (EOS) radioactive concentration (RAC) of at least 1,000 MBq/mL, and comprising no more than 150 μg/mL hydroxyl-ACBC, wherein the composition is prepared without passing the reaction mixture through an alumina solid phase. 
     
     
         23 . The PET tracer composition as defined in  claim 22 , wherein the composition has an end of synthesis (EOS) radioactive concentration (RAC) of at least 1500 MBq/mL. 
     
     
         24 . The PET tracer composition as defined in  claim 22 , wherein the composition has no more than 80 μg/mL hydroxyl-ACBC. 
     
     
         25 . The pharmaceutical composition as defined in  claim 22  comprising 50-100 mM citrate buffer. 
     
     
         26 . The pharmaceutical composition as defined in  claim 22  comprising 60-90 mM citrate buffer. 
     
     
         27 . The pharmaceutical composition as defined in  claim 22  comprising 75-85 mM citrate buffer. 
     
     
         28 . The pharmaceutical composition as defined in  claim 22  that has a pH of 4.0-5.0. 
     
     
         29 . The pharmaceutical composition as defined in  claim 22  that has a pH of 4.1-4.5. 
     
     
         30 . The pharmaceutical composition as defined in  claim 22  which comprises not more than 0.15 μg/mL 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC). 
     
     
         31 . The pharmaceutical composition as defined in  claim 22  which comprises not more than 0.10 μg/mL FACBC. 
     
     
         32 . The pharmaceutical composition as defined in  claim 22  which comprises not more than 2.0 μg/mL 1-amino-3-chloro-cydobutane-1-carboxylic acid (chloro-ACBC). 
     
     
         33 . The pharmaceutical composition as defined in  claim 22  which comprises not more than 1.0 μg/mL chloro-ACBC. 
     
     
         34 . A method of preparation of a PET tracer composition comprising (a) reacting in a reaction vessel a source of  18 F-fluoride with a precursor compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 LG is a leaving group; 
 PG 1  is a carboxy protecting group; 
 and, PG 2  is an amine protecting group; 
 
       to obtain a reaction mixture comprising a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein PG 1  and PG 2  are as defined for Formula I;
 (b) carrying out removal of PG 1  to obtain a reaction mixture comprising a compound of Formula III: 
 
       
         
           
           
               
               
           
         
       
       wherein PG 1  is as defined for Formula I;
 (c) carrying out removal of PG 2  to obtain a reaction mixture comprising  18 F-FACBC; and 
 (d) purifying said reaction mixture comprising  18 F-FACBC by passing it through a hydrophilic lipophilic balanced (HLB) solid phase, wherein said purifying does not comprise passing the reaction mixture comprising  18 F-FACBC through an alumina solid phase. 
 
     
     
         35 . The method as defined in  claim 34  wherein LG is trifluoromethanesulfonic acid. 
     
     
         36 . The method as defined in  claim 34  wherein PG 1  is ethyl. 
     
     
         37 . The method as defined in  claim 34  wherein PG 2  is t-butoxycarbonyl. 
     
     
         38 . The method as defined in  claim 34  wherein PG 1  is removed using NaOH. 
     
     
         39 . The method as defined in  claim 34  wherein PG 2  is removed using HCl. 
     
     
         40 . The method as defined  claim 34  further comprising formulating said purified reaction mixture obtained in step (d) with citrate buffer.