18f-labelled folates

Abstract

The present invention is directed towards a new method of synthesis of 18 F-folate radiopharmaceuticals, wherein fluorine-18 is attached to a pteroate (or folate) or derivative thereof, through direct radiolabeling with 18 [F]fluoride, as well as 18 F-folate radiopharmaceuticals obtained by such method of synthesis and their use in diagnosis and monitoring of cancer therapy and therapy of inflammatory and autoimmune diseases.

1 . A method of synthesis of an  18 F-labeled compound of general formula I 
     
       
         
         
             
             
         
       
       wherein 
       P is a pteroate, and 
       S 1  is a spacer, 
       comprising the steps of (a) providing a precursor of formula II, 
     
     
       
         
         
             
             
         
       
       wherein Z is a leaving group, and P and S 1  are defined as hereinabove, 
       and (b) subjecting said precursor to direct radiolabeling with  18 F to obtain a compound of formula I. 
     
   
   
       2 . A method according to  claim 1 , wherein S 1  is a straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof. 
   
   
       3 . A method according to  claim 1 , wherein  18 F in step (b) is activated by phase transfer catalysts such as tetrabutylammonium carbonate or aminopolyethers (e.g. Kryptofix© 2.2.2) in combination with potassium carbonate or oxalate. 
   
   
       4 . A method according to  claim 1 , wherein Z is selected from Hal, NO 2 , diazonium salts, sulfonate esters, including mesylate, tosylate, pentafluorobenzoate, triflate, iodonium salts, dialkyl/-aryl silanes, and silanols. 
   
   
       5 . A method according to  claim 1  wherein the obtained compound of general formula I has the formula III 
     
       
         
         
             
             
         
       
       wherein 
       X 1  to X 5  are independently of each other C or N, 
       R 1 , R 2  are independently of each other H, Hal, —OR′, —NHR′, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, 
       R 3 , R 4  are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, halosubstituted C1-C12 alkanoyl, 
       R 5  is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, (C1-C12 alkylamino)carbonyl, 
       S 1  is a straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof, 
       p is 0, 1 or 2, and 
       q has a value of 1 to 7. 
     
   
   
       6 . A method of synthesis according to  claim 1  of a  18 F-labeled compound of general formula III 
     
       
         
         
             
             
         
       
       wherein 
       X 1  to X 5  are independently of each other C or N, 
       R 1 , R 2  are independently of each other H, Hal, —OR′, —NHR′, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, 
       R 3 , R 4  are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, halosubstituted C1-C12 alkanoyl, 
       R 5  is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, (C1-C12 alkylamino)carbonyl, 
       S 1  is a straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof, 
       p is 0, 1 or 2, and 
       q has a value of 1 to 7, 
       comprising the steps of (a) providing a precursor of formula IV, 
     
     
       
         
         
             
             
         
       
     
     wherein Z is a leaving group, and X 1  to X 5 , R 1  to R 5 , S 1 , p, and q are defined as hereinabove, and (b) subjecting said precursor to direct radiolabeling with  18 F. 
   
   
       7 . A method according to  claim 7 , wherein S 1  is straight-chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof. 
   
   
       8 . A method according to  claim 7 , wherein  18 F in step (b) is activated by phase transfer catalysts such as tetrabutylammonium carbonate or aminopolyethers (e.g. Kryptofix© 2.2.2) in combination with potassium carbonate or oxalate. 
   
   
       9 . A method according to  claim 6 , wherein Z is selected from Hal, NO 2 , diazonium salts, sulfonate esters, including mesylate, tosylate, pentafluorobenzoate, triflate, iodonium salts, dialkyl/-aryl silanes, and silanols. 
   
   
       10 . A method according to  claim 1 , wherein the obtained compound has the formula V 
     
       
         
         
             
             
         
       
       wherein 
       X 6 , X 7  are independently of each other N or O, 
       R 6 , R 7  are independently of each other H, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal or NO 2 , or a group —S 2 — 18 F, wherein S 2  is straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof, 
       with the proviso that at least one of R 6  and R 7  is a group —S 2 — 18 F, and 
       X 1  to X 5 , R 1  to R 5 , p and q, are as defined in  claim 1 . 
     
   
   
       11 . A method according to  claim 10 , wherein S 2  is straight chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof. 
   
   
       12 . A method according to  claim 1 , wherein the obtained compound has the formulae VI or VIa, 
     
       
         
         
             
             
         
       
       wherein 
       X 1  to X 5  are independently of each other C or N, 
       X 6 , X 7  are independently of each other C, O or N, 
       R 1 , R 2  are independently of each other H, Hal, —OR′, —NHR′, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, 
       R 3 , R 4  are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, halosubstituted C1-C12 alkanoyl, 
       R 5  is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl, 
       R 6 , R 7  are independently of each other H or straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , 
       S 2  is straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof, 
       p is 0, 1 or 2, and 
       q has a value of 1 to 7. 
     
   
   
       13 . A method of synthesis according to  claim 1  of a  18 F-labeled compound of general formulae VI or VIa, 
     
       
         
         
             
             
         
       
       wherein 
       X 1  to X 5  are independently of each other C or N, 
       X 6 , X 7  are independently of each other C, O or N, 
       R 1 , R 2  are independently of each other H, Hal, —OR′, —NHR′, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, 
       R 3 , R 4  are independently of each other H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, halosubstituted C1-C12 alkanoyl, 
       R 5  is H, CN, Hal, NO 2 , C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl, 
       R 6 , R 7  are independently of each other H or straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , 
       S 2  is straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof, 
       p is 0, 1 or 2, and 
       q has a value of 1 to 7, 
       comprising the steps of 
       (a) providing a precursor of formulae VII or VIIa, 
     
     
       
         
         
             
             
         
       
       wherein Z is a leaving group, and X 1  to X 7 , R 1  to R 7 , S 2 , p, and q are defined as hereinabove, and (b) subjecting said precursor to direct radiolabeling with  18 F. 
     
   
   
       14 . A method according to  claim 12 , wherein S 2  is straight chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof. 
   
   
       15 . A method according to  claim 1 , wherein the obtained compound has the formulae VIII or VIIIa, 
     
       
         
         
             
             
         
       
       wherein, 
       X 6 , X 7  are independently of each other C, N or O, 
       Y 1 , Y 2  are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , 
       Y 3  is selected from H, formyl, nitroso, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , 
       R 6 , R 7  are independently of each other H or straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and 
       S 2  is straight-chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of the non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —N═, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C C—, —S—, —SO 3 R′—, —PR′—, or a five- or six-membered aromatic ring having 0, 1 or 2 heteroatoms, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof. 
     
   
   
       16 . A method according to  claim 15 , wherein S 2  is straight-chain or branched C1-C8 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , or a five- or six-membered aromatic ring, which is unsubstituted or substituted with CN, Hal, NO 2 , COR′, or COOR′, wherein R′ represents H or C1-C6 alkyl, or a combination thereof. 
   
   
       17 . A compound of formula I obtainable by a method according to  claim 1 . 
   
   
       18 . A compound according to  claim 17  having formula III. 
   
   
       19 . A compound according to  claim 16  with the proviso that S 1  does not represent benzyl para-substituted with  18 F. 
   
   
       20 . (canceled) 
   
   
       21 . Method of  claim 22  for convenient and effective administration to a subject in need for diagnostic imaging. 
   
   
       22 . Method for diagnostic imaging of a cell or population of cells expressing a folate-receptor, said method comprising the steps of administering at least one compound according to  claim 17  in a diagnostic imaging amount, and obtaining a diagnostic image of said cell or population of cells. 
   
   
       23 . Method according to  claim 22 , wherein the diagnostic imaging is performed of a cell or population of cells expressing a folate-receptor in vitro or in vivo. 
   
   
       24 . Method for in vitro detection of a cell expressing the folate receptor in a tissue sample which includes contacting said tissue sample with a compound according to  claim 17  in effective amounts and for sufficient time and conditions to allow binding to occur and detecting such binding by PET imaging. 
   
   
       25 . Method of diagnostic imaging or monitoring a subject comprising the steps of (i) administering at least one compound according to  claim 17  in a diagnostic imaging amount, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound. 
   
   
       26 . Method of monitoring therapy of cancer or inflammatory and autoimmune diseases in a subject comprising the steps of (i) administering to a subject in need thereof at least one compound according to  claim 17  in a diagnostic imaging amount in combination with a therapeutically active, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound to follow the course of therapy of cancer or inflammatory and autoimmune diseases. 
   
   
       27 . Method of  claim 25  used in combination with any other methods of diagnosis or therapy of cancer or inflammatory and autoimmune diseases.