Compositions and methods related to serotonin 5-HT1A receptors
View Patent ↗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.