18f-labelled folates as pet radiotracers

Abstract

The present invention is directed towards new 18 F-folate radiopharmaceuticals, wherein fluorine-18 is covalently linked to the glutamate portion of a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of therapy of cancer and inflammatory and autoimmune diseases.

1 . A compound of formula I, 
       
         
           
           
               
               
           
         
       
       wherein
 P is a pteroyl group or derivative thereof, 
 X a , X b  are independently of each other C, N, O, S, 
 R a , R b  are independently of each other H or straight-chain or branched C 1 -C 12  alkyl, C 3 -C 6  cycloalkyl, C 5 -C 14  aryl or C 5 -C 14  heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO 2 —, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl; and 
 Z 1 , Z 2  are independently of each other H or  18 F, with the proviso that one of Z 1  and Z 2  is  18 F. 
 
     
     
         2 . A compound according to  claim 1  having formula II 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  to X 5  are independently of each other C or N, 
 R 1  and R 2  are independently of each other H, Hal, —OR′, —NR″R′″, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, C 1 -C 12  alkanoyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, (C 1 -C 12  alkoxy)carbonyl, and (C 1 -C 12  alkylamino)carbonyl, wherein R′ is H or C 1 -C 6  alkyl, and wherein R″ and R″′ are independently of each other selected from H, formyl, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl, 
 R 3 , R 4  are independently of each other H, formyl, trifluoroacetyl, iminomethyl, nitroso, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl, or R 3  and R 4  form together a C 1  or C 2 -bridge between X 3  and X 5 , 
 R 5  is H, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, C 1 -C 12  alkanoyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, (C 1 -C 12  alkoxy)carbonyl, and (C 1 -C 12  alkylamino)carbonyl, 
 m is 0 or 1, 
 p is 0, 1 or 2, 
 q has a value of 1 to 7 
 X a , X b  are independently of each other C, N, O, S, 
 R a , R b  are independently of each other H or straight-chain or branched C 1 -C 12  alkyl, C 3 -C 6  cycloalkyl, C 5 -C 14  aryl or C 5 -C 14  heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO 2 —, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl; and 
 Z 1 , Z 2  are independently of each other H or  18 F, with the proviso that one of Z 1  and Z 2  is  18 F. 
 
     
     
         3 . A compound according to  claim 1  having formulae IIIa, IIIb, IVa, or IVb, 
       
         
           
           
               
               
           
         
       
       wherein
 X 1  to X 5  are independently of each other C or N, 
 R 1  and R 2  are independently of each other H, Hal, —OR′, —NR″R′″, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, C 1 -C 12  alkanoyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, (C 1 -C 12  alkoxy)carbonyl, and (C 1 -C 12  alkylamino)carbonyl, wherein R′ is H or C 1 -C 6  alkyl, and wherein R″ and R″′ are independently of each other selected from H, formyl, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl, 
 R 3 , R 4  are independently of each other H, formyl, trifluoroacetyl, iminomethyl, nitroso, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl, or R 3  and R 4  form together a C 1  or C 2 -bridge between X 3  and X 5 , 
 R 5  is H, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, C 1 -C 12  alkanoyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, (C 1 -C 12  alkoxy)carbonyl, or (C 1 -C 12  alkylamino)carbonyl, 
 m is 0 or 1, 
 p is 0, 1 or 2, 
 q has a value of 1 to 7, 
 X a , X b  are independently of each other C, N, O, S, 
 R a , R b  are independently of each other H or straight-chain or branched C 1 -C 12  alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO 2 —, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl. 
 
     
     
         4 . A compound according to  claim 1 , wherein R 1  and R 2  are independently of each other H, alkyl, —OR′, —NHR′, wherein R′ represents H or C 1 -C 6  alkyl. 
     
     
         5 . A compound according to  claim 1 , wherein R 3  is H, formyl, C1-C12 alkyl or C1-C12 alkanoyl. 
     
     
         6 . A compound according to  claim 1 , wherein R 3  is H, formyl, or methyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 4  is H, formyl, nitroso, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  alkanoyl. 
     
     
         8 . A compound according to  claim 1 , wherein R 4  is H, formyl, or methyl. 
     
     
         9 . A compound according to  claim 1 , wherein R 5  is H, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, C 1 -C 12  alkanoyl, (C 1 -C 12  alkoxy)carbonyl, or (C 1 -C 12  alkylamino)carbonyl. 
     
     
         10 . A compound according to  claim 1 , wherein R 5  is H. 
     
     
         11 . A compound according to  claim 1  having formulae Va, Vb, VIa or VIb, 
       
         
           
           
               
               
           
         
       
       wherein,
 X a , X b  are independently of each other C, N, O, S, 
 R a , R b  are independently of each other H or straight-chain or branched C 1 -C 12  alkyl, C 3 -C 6  cycloalkyl, C 5 -C 14  aryl or C 5 -C 14  heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO 2 —, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl; 
 Y 1 , Y 2  are independently of each other selected from H, formyl, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl, 
 Y 3  is selected from H, formyl, trifluoroacetyl, nitroso, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl. 
 
     
     
         12 . A compound according to  claim 1  having formulae VIIa, VIIb, VIIIa or VIIIb, 
       
         
           
           
               
               
           
         
       
       wherein,
 X a , X b  are independently of each other C, N, O, S, 
 R a , R b  are independently of each other H or straight-chain or branched C 1 -C 12  alkyl, C 3 -C 6  cycloalkyl, C 5 -C 14  aryl or C 5 -C 14  heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO 2 —, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl; 
 p is 0, 1 or 2, 
 Y 1 , Y 2  are independently of each other selected from H, formyl, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl, 
 R 3  is H, formyl, iminomethyl, nitroso, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, C 1 -C 12  alkanoyl, halosubstituted C 1 -C 12  alkanoyl, and 
 Y 3  is selected from H, formyl, trifluoroacetyl, nitroso, straight chain or branched C 1 -C 12  alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO 2 , and wherein one or more of embedded, non-adjacent CH 2  groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1 -C 6  alkyl, or 
 R 3  and Y 3  form together a C 1  or C 2 -bridge between the two N-atoms to which they are attached to. 
 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . 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 1  in a diagnostic imaging amount, and obtaining a diagnostic image of said cell or population of cells. 
     
     
         16 . Method according to  claim 15 , wherein the diagnostic imaging is performed of a cell or population of cells expressing a folate-receptor in vitro or in vivo. 
     
     
         17 . 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 1  in effective amounts and for sufficient time and conditions to allow binding to occur and detecting such binding by PET imaging. 
     
     
         18 . Method of diagnostic imaging or monitoring a subject comprising the steps of (i) administering at least one compound according to  claim 1  in a diagnostic imaging amount, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound. 
     
     
         19 . Method of monitoring therapy of cancer and 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 1  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 and inflammatory and autoimmune diseases. 
     
     
         20 . Method of  claim 15  used in combination with any other methods of diagnosis or therapy of cancer and inflammatory and autoimmune diseases.