Pet Radiotracers

Abstract

The invention relates to novel 18 F-labelled compounds which may be suitable for use as Positron Emission Tomography (PET) radiotracers, and to processes for preparation of such. The 18 F-labelled compounds of the invention comprise a [ 18 F]fluoroalkenyl group.

1 . A compound comprising a [ 18 F]fluoroalkenyl group. 
   
   
       2 . A compound as claimed in  claim 1  of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
       X′ and X″ are independently selected from hydrogen and  18 F, with the proviso that either X′ or X″ is a  18 F-atom; 
       n is an integer from 1 to 5; 
       the vector comprises a moiety having affinity for a biological target; and 
       L represents a linker moiety. 
     
   
   
       3 . A compound as claimed in  claim 2  wherein the vector is a biomolecule selected from the group consisting of peptides, peptoids/peptidomimetics and proteins; oligonucleotides; oligosaccharides; lipid-related compounds; hormones; synthetic small drug-like molecules; inhibitors; antibodies and antibody fragments; and derivatives and mimetics thereof. 
   
   
       4 . A compound as claimed in  claim 1  wherein the linker is a covalent bond or comprises moieties selected from the group consisting of amines, amides, thioethers, ethers, sulfones, sulfoxides, sulfides, polyalkyleneglycols, polylactic acids and polyglycolic acid moieties and amino acids. 
   
   
       5 . A compound as claimed in  claim 1  of formula (IIa) 
     
       
         
         
             
             
         
       
       wherein 
       R1 to R8 are independently selected from hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -haloalkoxy, hydroxyl, cyano and nitro; 
       R9 and R10 are independently selected from hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl and C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl; 
       and wherein 
       one of the groups R1 to R10 comprises a group of formula (IIb) 
     
     
       
         
         
             
             
         
       
       wherein X′, X″ and n are as defined in formula (I). 
     
   
   
       6 . A compound as claimed in  claim 1  of formula (III) 
     
       
         
         
             
             
         
       
       wherein 
       X′, X″ and n are as defined in formula I. 
     
   
   
       7 . A compound as claimed in  claim 1  of formula (IV) 
     
       
         
         
             
             
         
       
       wherein 
       X′ and X″ are defined as in formula (I); 
       R′ and R″ are individually selected from hydrogen and lower alkyl; and 
       Z represents a halogen atom. 
     
   
   
       8 . A process for the preparation of a compound according to  claim 1  by fluorinating an alkenyl(aryl)iodonium salt with  18 F-fluoride. 
   
   
       9 . A process as claimed in  claim 8  wherein the alkenyl(aryl)iodonium salt is an alkenyl(aryl)iodonium salt of formula (VI), 
     
       
         
         
             
             
         
       
       wherein 
       I + -Aryl represents a phenyliodonium salt, wherein the aryl group is optionally substituted with methoxy, ethoxy, propyloxy, tert-butyloxy, halides or C 1 -C 6 -alkyl groups; and 
       the vector, L and n are defined as in formula I. 
     
   
   
       10 . A process as claimed in  claim 8  wherein the alkenyl(aryl)iodonium salt is prepared by
 i) reacting a vector moiety, optionally comprising a protecting group, with an alkyne to prepare a compound comprising a vector moiety linked to an alkyne group;   ii) hydrometalating the alkyne group of the compound from step (i) to prepare a metalated alkene;   iii) reacting the metalated alkene of step (ii) with an iodonium transfer reagent to prepare the alkenyl(aryl)iodonium salt.   
   
   
       11 . A process as claimed in  claim 8  optionally followed by
 a) removal of excess  18 F—; and/or   b) removal of any protecting groups; and/or   c) removal of organic solvents; and/or   d) formulation of the resultant  18 F-labelled compound of the invention as an aqueous solution.   
   
   
       12 . A process for preparation of a compound according to  claim 1  by cross metathesis reacting a  18 F-fluoroethene with a compound comprising a terminal alkene group in the presence of a Grubbs catalyst. 
   
   
       13 . A process as claimed in  claim 12  carried out in a one-pot tandem reaction wherein a  18 F-fluoroethyl comprising a leaving group is added to a solution of palladium(0) and a Grubbs catalyst to prepare  18 F-fluoroethene, followed by addition of a compound comprising a terminal alkene group. 
   
   
       14 . A process as claimed in  claim 12  wherein the compound comprising a terminal alkene group is a vector moiety comprising a terminal alkene group. 
   
   
       15 . A compound as claimed in  claim 1  for use as a PET radiotracer. 
   
   
       16 . A pharmaceutical composition comprising a compound as claimed in  claim 1  together with one or more pharmaceutically acceptable adjuvants, excipients or diluents. 
   
   
       17 . A method for obtaining a PET image using a compound as claimed in  claim 1 . 
   
   
       18 . A radiopharmaceutical kit for the preparation of a compound according to  claim 1 , which comprises
 i) a first vessel containing a precursor of a [ 18 F]fluoroalkenylated compound of  claim 1 ;   ii) a second vessel with means for eluting the first vessel with a source of  18 F.