Compositions and methods related to serotonin 5-HT1A receptors

Abstract

Contemplated substituted arylpiperazinyl compounds, and most preferably 18 F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with 18 F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

1. A compound having a structure according to Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof;  
         wherein R 1  is OCH 3  or O 11 CH 3  alkoxy; 
         X is N, and W is CH; 
         Y is O, and wherein * denotes an optional  11 C isotope; 
         Q is optionally substituted cycloalkyl or cycloalkenyl; and 
         wherein Z is lower alkyl, and wherein  18 F is covalently bound to Z when  11 C is absent in *; and 
         wherein  11 C is present in at least one of R 1  and * when  18 F is absent and Z is CH 2 F. 
       
     
     
       2. The compound of  claim 1  fun her comprising a pharmaceutically acceptable carrier in admixture with the compound to form a pharmaceutical composition, wherein the compound is optionally present as a salt with a pharmaceutically acceptable counter ion. 
     
     
       3. A method of diagnosing or treating a panic disorder, a bipolar disorder, or a seizure disorder, comprising a step of administering a pharmaceutical composition that includes a compound having a structure according to Formula I, or a pharmaceutically acceptable salt thereof, to a mammal, 
       
         
           
           
               
               
           
         
         wherein R 1  is an optionally substituted lower alkyl, alkoxy, halogen, or hydrogen, and wherein at least one carbon atom in R1 may be  11 C; 
         X and W are independently N or CH; 
         Y is O, NR 1 , or S, and wherein * denotes an optional  11 C isotope; 
         Q is optionally substituted cycloalkyl or cycloalkenyl; and 
         wherein Z is lower alkyl, and wherein a PET detectable label is covalently bound to Z when  11 C is absent in R 1  and *, and wherein the PET detectable label is  11 C or  18 F. 
       
     
     
       4. The method of  claim 3  wherein in the compound Q is cyclohexyl or cyclohexenyl, and Z is CH 2   18  or CH 2 CH 2    18 F. 
     
     
       5. The method of  claim 3  wherein in the compound comprises  18 F-Mefway the compound is 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       6. The method of  claim 5  wherein in the compound comprises the compound is trans- 18 F-Mefway  
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       7. The method of  claim 3  further comprising a step of performing at least one of a PET scan and a SPECT scan on the mammal. 
     
     
       8. The method of  claim 3  wherein the pharmaceutical composition is parenterally administered. 
     
     
       9. The method of  claim 3  wherein the composition comprises  18 F-Mefway  
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       10. The method of  claim 3  wherein the composition comprises trans- 18 F-Mefway 
       
         
           
           
               
               
           
         
       
     
     
       11. A method of quantifying serotonin in a neural tissue comprising:
 a step of administering a pharmaceutical composition comprising a compound having a structure according to Formula I, or a pharmaceutically acceptable salt thereof, to a mammal, 
 
       
         
           
           
               
               
           
         
         wherein R 1  is an optionally substituted lower alkyl, alkoxy, halogen, or hydrogen, and wherein at least one carbon atom in R1 may be  11 C; 
         X and W are independently N or CH; 
         Y is O, NR 1 , or S, and wherein * denotes an optional  11 C isotope; 
         Q is optionally substituted cycloalkyl or cycloalkenyl; and 
         wherein Z is lower alkyl, and wherein a PET detectable label is covalently bound to Z when  11 C is absent in R 1  to *, and wherein the PET detectable label is  11 C or  18 F, and wherein Z is CH 2 F when  11 C is present in R 1  or *;  
         a step of performing a PET scan on the tissue, and 
         a step of correlating a PET signal quantity with a serotonin concentration in the tissue. 
       
     
     
       12. The method of  claim 11  wherein in the compound Q is cyclohexyl or cyclohexenyl, and Z is CH 2    18 F or CH 2 CH 2    18 F. 
     
     
       13. A compound having a structure according to Formula II 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       14. A compound having a structure according to Formula III 
       
         
           
           
               
               
           
         
         wherein L is a leaving group.  
       
     
     
       15. The compound of claim 14 wherein L is selected from the group consisting of halogen, O-mesylate, O-tosylate, O-nosylate, and O-brosylate.  
     
     
       16. A method for imaging the 5-HT1A receptor comprising:
 (i) administering a pharmaceutical composition comprising a compound having a structure according to Formula I to a mammal   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein R 1  is an optionally lower alkyl, alkoxy, halogen, or hydrogen, and wherein at least one carbon atom in R 1  is optionally  11 C; 
         X and W are independently N or CH; 
         Y is O, NR 1 , or S, and wherein * denotes an optional  11 C isotope; 
         Q is optionally substituted cycloalkyl or cycloalkenyl; and 
         Z is lower alkyl, and 
         wherein a PET detectable label is covalently bound to Z when  11 C is absent in R 1  and *, and wherein the PET detectable label is  11 C or  18 F, and wherein Z is CH 2 F when  11 C is present in R 1  or *; and
 (ii) performing a PET scan on said mammal.  
 
       
     
     
       17. A method of quantifying serotonin in vivo comprising:
 (i) administering a pharmaceutical composition comprising a compound having a structure according to Formula I, or a pharmaceutically acceptable salt thereof, to a mammal   
       
         
           
           
               
               
           
         
         wherein R 1  is an optionally lower alkyl, alkoxy, halogen, or hydrogen, and wherein at least one carbon atom in R1 is optionally  11 C; 
         X and W are independently N or CH; 
         Y is O, NR 1 , or S, and wherein * denotes an optional  11 C isotope; 
         Q is optionally substituted cycloalkyl; and 
         Z is lower alkyl, and 
         wherein a PET detectable label is covalently bound to Z when  11 C is absent in R 1  and * and wherein the PET detectable label is  11 C or  18 F, and wherein Z is CH 2 F when  11 C is present in R 1  or *;
 (ii) performing a PET scan on said mammal; and 
 (iii) correlating a PET signal quantity with a serotonin concentration.  
 
       
     
     
       18. A ligand-receptor complex comprising:
 (i) a compound having a structure according to Formula I   
       
         
           
           
               
               
           
         
         wherein R 1  is an optionally lower alkyl, alkoxy, halogen, or hydrogen, and wherein at least one carbon atom in R 1  is optionally  11 C; 
         X and W are independently N or CH; 
         Y is O, NR 1 , or S, and wherein * denotes an optional  11 C isotope; 
         Q is optionally substituted cycloalkyl; and 
         Z is lower alkyl, and 
         wherein a PET detectable label is covalently bound to Z when  11 C is absent in R 1  and *, and wherein the PET detectable label is  11 C or  18 F, and wherein Z is CH 2 F when  11 C is present in R 1  or *; and
 (ii) a 5-HT1A receptor.