Metal complexes and fluorination thereof

Abstract

A method of labelling biological molecules with 18 F, via attachment of fluorine to a metal complex, where the metal complex is conjugated to the biological molecule. The invention highlights the incorporation of hydrogen bonding (H-bonding) into the metal complex scaffold, and how this can be utilized to improve the kinetics of fluoride incorporation. Also provided are pharmaceutical compositions, kits and methods of in vivo imaging.

1 - 21 . (canceled) 
     
     
         22 . A method of preparation of an imaging agent which comprises an  18 F-labelled compound of Formula I: 
       
         
           
           
               
               
           
         
       
       where:
 X 1 , X 2  and X 3  are independently Br, Cl,  19 F or  18 F, with the proviso that at least one of X 1 , X 2  and X 3  is  18 F; 
 M is Al 3+ , Ga 3+ , In 3+ , Sc 3+ , Y 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+  or Lu 3+ ; 
 Z 1  is of Formula Z a   
 
       
         
           
           
               
               
           
         
         where each R 3  is independently H, C 1-4  alkyl, C 2-4  alkoxyalkyl, C 1-4  hydroxyalkyl, a Y group or a Q group; 
         each f is independently 1; 
         p is 1, 2 or 3; 
         y is 0 or 1; 
         Y is independently -(A′) x -Y 1  or -(A′) x -Y 1 -Q where each A 1  is independently —CH 2 — or —O—, provided that Y does not comprise any —O—O— bonds; 
         wherein x is an integer of value 1 to 6; and 
         Y 1  is —NHR a , —NH(CH 2 ) 2 NHR a , —NH(CH 2 ) 3 NHR a , —(C═O)NHR a , —NH(C═O)R a , —NH(C═NH)NHR a , —OR a  or a Y 3  group; 
         Y 3  is Arg, Lys, Asn, Gln, Ser, Thr or Tyr; 
         wherein R a  is independently H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  alkoxyalkyl or C 1-4  hydroxyalkyl; 
         Q is -L-[BTM]; 
         L is a synthetic linker group of formula -(A) m - wherein each A is independently —CR 2 —, —CR═CR—, —C≡C—, —CR 2 CO 2 —, —CO 2 CR 2 —, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR 2 OCR 2 —, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8  cycloheteroalkylene group, a C 4-8  cycloalkylene group, —Ar—, —NR—Ar—, —O—Ar—, —Ar—(CO)—, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block, 
         wherein each R is independently chosen from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  alkoxyalkyl or C 1-4  hydroxyalkyl; 
         m is an integer of value 1 to 20; 
         each Ar is independently a C 5-12  arylene group, or a C 3-12  heteroarylene group; 
         BTM is a biological targeting moiety chosen from: a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist, an enzyme agonist, an enzyme inhibitor or a receptor-binding compound, 
         wherein the method comprising reaction of a precursor with a supply of [ 18 F]-fluoride or [ 18 F]NaF, optionally in the presence of [ 19 F]-fluoride, in a suitable solvent, 
         wherein said precursor of Formula III comprises a metal complex of a chelator of Formula II: 
       
       
         
           
           
               
               
           
         
         where Z 1 , Y, Q, p and q are as defined in Formula Z a ; 
       
       
         
           
           
               
               
           
         
         where X 1a , X 2a  and X 3a  are independently Br or Cl; and 
         where said metal is chosen from: Al 3+ , Ga 3+ , In 3+ , Sc 3+ , Y 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+  or Lu 3+ . 
       
     
     
         23 . The method of  claim 22 , where one Q group is present in the imaging agent. 
     
     
         24 . The method of  claim 22 , where each Y group is covalently conjugated to a different amine donor atom of Z 1  in the imaging agent. 
     
     
         25 . The method of any one of  claim 22 , where in the imaging agent Z a  is of Formula Z aa  or Z ab : 
       
         
           
           
               
               
           
         
       
       where R 4  is H, C 1-4  alkyl, C 2-4  alkoxyalkyl, C 1-4  hydroxyalkyl or a Y group; 
       R 5  is H, C 1-4  alkyl, C 2-4  alkoxyalkyl or C 1-4  hydroxyalkyl. 
     
     
         26 . The method of any one of  claim 22 , where M is Ga 3+  or In 3+  in the imaging agent. 
     
     
         27 . The method of any one of  claim 22 , where X 1 , X 2  and X 3  are independently Cl,  19 F or  18 F in the imaging agent. 
     
     
         28 . The method of any one of  claim 22 , where X 1a ═X 2a ═X 3a ═Cl. 
     
     
         29 . A chelating agent for use in producing an imaging agent which comprises an  18 F-labelled compound of Formula I: 
       
         
           
           
               
               
           
         
       
       where:
 X 1 , X 2  and X 3  are independently Br, Cl,  19 F or  18 F, with the proviso that at least one of X 1 , X 2  and X 3  is  18 F; 
 M is Al 3+ , Ga 3+ , In 3+ , Sc 3+ , Y 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+  or Lu 3+ ; 
 Z 1  is of Formula Z a   
 
       
         
           
           
               
               
           
         
         where each R 3  is independently H, C 1-4  alkyl, C 2-4  alkoxyalkyl, C 1-4  hydroxyalkyl, a Y group or a Q group;
 each f is independently 1; 
 
         p is 1, 2 or 3; 
         y is 0 or 1; 
         Y is independently -(A 1 ) x -Y 1  or -(A 1 ) x -Y 1 -Q where each A 1  is independently —CH 2 — or —O—, provided that Y does not comprise any —O—O— bonds; 
         wherein x is an integer of value 1 to 6; and 
         Y 1  is —NHR a , —NH(CH 2 ) 2 NHR a , —NH(CH 2 ) 3 NHR a , —(C═O)NHR a , —NH(C═O)R a , —NH(C═NH)NHR a , —OR a  or a Y 3  group; 
         Y 3  is Arg, Lys, Asn, Gln, Ser, Thr or Tyr; 
         wherein R a  is independently H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  alkoxyalkyl or C 1-4  hydroxyalkyl; 
         Q is -L-[BTM]; 
         L is a synthetic linker group of formula -(A) m - wherein each A is independently —CR 2 —, —CR═CR—, —C═C—, —CR 2 CO 2 —, —CO 2 CR 2 —, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR 2 OCR 2 —, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8  cycloheteroalkylene group, a C 4-8  cycloalkylene group, —Ar—, —NR—Ar—, —O—Ar—, —Ar—(CO)—, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block, 
         wherein each R is independently chosen from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  alkoxyalkyl or C 1-4  hydroxyalkyl; 
         m is an integer of value 1 to 20; 
         each Ar is independently a C 5-12  arylene group, or a C 3-12  heteroarylene group; BTM is a biological targeting moiety chosen from: a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist, an enzyme agonist, an enzyme inhibitor or a receptor-binding compound, 
         wherein the chelating agent of Formula IIA: 
       
       
         
           
           
               
               
           
         
       
       and
 where Z 1 , Y, Q, p and q are as defined in Formula I. 
 
     
     
         30 . A metal complex of the chelating agent of Formula IIA as defined in  claim 29 , where said metal is Al 3+ , Ga 3+ , In 3+ , Sc 3+ , Y 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+  or Lu 3+ .