RADIOLABELED COMPOUNDS AND USES THEREOF
20220106275 · 2022-04-07
Inventors
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07B2200/05
CHEMISTRY; METALLURGY
International classification
C07D261/08
CHEMISTRY; METALLURGY
C07D409/12
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
Abstract
Radiolabeled compounds of Formula I are described. Processes for radiolabeling the compounds are described. Methods for radioactive imaging using the compounds are also described.
Claims
1. A compound of Formula I: ##STR00206## or a pharmaceutically acceptable salt thereof, wherein: A is ##STR00207## R is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2; wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of hydrogen, deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, and NHCOR.sup.5; wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5; and each occurrence of R.sup.5 is independently selected from the group consisting of hydrogen, deuterium, .sup.3H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl; wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, or .sup.131I; wherein at least one of R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, or R.sup.5 comprises at least one of .sup.3H, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, or .sup.131I; wherein when A is ##STR00208## R is .sup.11CH.sub.3, R.sup.1 is hydrogen, and R.sup.2 is phenyl, R.sup.4 is not CF.sub.3; wherein when A is ##STR00209## R is CH.sub.3, R.sup.1 and R.sup.2 are hydrogen, and R.sup.3 is CF.sub.3, R.sup.4 is not ##STR00210## and wherein when A is ##STR00211## R is CH.sub.3, R.sup.1 and R.sup.3 are hydrogen, and R.sup.4 is O.sup.11CH.sub.3, R.sup.2 is not ##STR00212##
2. The compound of claim 1, wherein A is ##STR00213##
3. The compound of claim 1, wherein A is ##STR00214##
4. The compound of claim 1, wherein A is ##STR00215##
5. The compound of claim 1, wherein R is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2; wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I.
6. The compound of claim 5, wherein each occurrence of R.sup.5 is independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl; wherein each (C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I.
7. The compound of claim 6, wherein R is CH.sub.3, .sup.11CH.sub.3, CH.sub.2.sup.18F, (CH.sub.2).sub.2.sup.18F, CF.sub.3, CF.sub.2.sup.18F, CD.sub.2.sup.18F, ##STR00216## wherein each ##STR00217## is optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I.
8. The compound of claim 7, wherein R is CH.sub.3, .sup.11CH.sub.3, or (CH.sub.2).sub.2.sup.18F.
9. The compound of claim 1, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2; wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I.
10. The compound of claim 9, wherein each occurrence of R.sup.5 is independently selected from the group consisting of hydrogen, deuterium, (C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl; wherein each (C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I.
11. The compound of claim 10, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen, deuterium, halogen, .sup.18F, .sup.123I, CH.sub.3, .sup.11CH.sub.3, CH.sub.2.sup.18F, (CH.sub.2).sub.2.sup.18F, CF.sub.3, CF.sub.2.sup.18F, CD.sub.2.sup.18F, ##STR00218## wherein each ##STR00219## is optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I.
12. The compound of claim 11, wherein R.sup.1 is hydrogen or .sup.18F.
13. The compound of claim 11, wherein R.sup.2 is hydrogen, ##STR00220##
14. The compound of claim 11, wherein R.sup.3 is hydrogen or .sup.18F.
15. The compound of claim 11, wherein R.sup.4 is halogen, .sup.18F, CF.sub.2.sup.18F, CH.sub.2.sup.18F, CD.sub.2.sup.18F, CF.sub.3, ##STR00221##
16. The compound of claim 1, wherein: A is ##STR00222## R is CH.sub.3 or .sup.11CH.sub.3; R.sup.1 and R.sup.3 are hydrogen; R.sup.2 is N(R.sup.5).sub.2; R.sup.4 is F, Cl, CF.sub.3, or .sup.18F; and each occurrence of R.sup.5 is independently hydrogen, (C.sub.1-C.sub.6)alkyl-aryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl.
17. The compound of claim 16, wherein each occurrence of R.sup.5 is independently hydrogen, ##STR00223##
18. The compound of claim 17, wherein R.sup.2 is ##STR00224##
19. The compound of claim 1, wherein: A is ##STR00225## R is CH.sub.3; R.sup.1 and R.sup.2 are hydrogen; R.sup.2 is .sup.18F; R.sup.4 is (NR.sup.5).sub.2; and each occurrence of R.sup.5 is independently hydrogen, (C.sub.1-C.sub.6)alkyl-aryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl.
20. The compound of claim 19, wherein each occurrence of R.sup.5 is independently hydrogen, ##STR00226##
21. The compound of claim 20, wherein R.sup.2 is ##STR00227##
22. The compound of claim 1, wherein: A is ##STR00228## R and R.sup.4 are (C.sub.1-C.sub.6)alkyl, optionally substituted with one or more deuterium, .sup.18F, or halogen; R.sup.1 is hydrogen or .sup.18F; R.sup.2 is aryl, optionally substituted with .sup.18F, or heteroaryl, optionally substituted with .sup.18F.
23. The compound of claim 22, wherein R is CH.sub.3 or (CH.sub.2).sub.2.sup.18F.
24. The compound of claim 22, wherein R.sup.2 is ##STR00229##
25. The compound of claim 22, wherein R.sup.4 is CF.sub.3, CF.sub.2.sup.18F, CH.sub.2.sup.18F.
26. The compound of claim 1, wherein the compound of Formula I is ##STR00230## or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1, wherein the compound of Formula I is ##STR00231## or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1, wherein the compound of Formula I is ##STR00232## or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1, wherein the compound of Formula I is ##STR00233## or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1, wherein the compound of Formula I is ##STR00234## or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1, wherein the compound of Formula I is ##STR00235## or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1, wherein the compound of Formula I is ##STR00236## or a pharmaceutically acceptable salt thereof.
33. The compound of claim 1, wherein the compound of Formula I is ##STR00237## or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1, wherein the compound of Formula I is ##STR00238## or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1, wherein the compound of Formula I is ##STR00239##
36. The compound of claim 1, wherein the compound of Formula I is ##STR00240##
37. The compound of claim 1, wherein the compound of Formula I is ##STR00241##
38. The compound of claim 1, wherein the compound of Formula I is ##STR00242##
39. The compound of claim 1, wherein the compound of Formula I is ##STR00243##
40. The compound of claim 1, wherein the compound of Formula I is ##STR00244##
41. The compound of claim 1, wherein the compound of Formula I is ##STR00245##
42. The compound of claim 1, wherein the compound of Formula I is ##STR00246##
Description
BRIEF DESCRIPTION OF THE FIGURES
[0162] The invention is described with reference to the following figures, which are presented for the purpose of illustration only and are not intended to be limiting. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the United States Patent and Trademark Office upon request and payment of the necessary fee.
[0163]
[0164]
[0165]
[0166]
[0167]
[0168]
[0169]
[0170]
[0171]
[0172]
DETAILED DESCRIPTION OF THE INVENTION
[0173] Radiolabeled compounds that interact with biomarkers (e.g., proteins) for disease are useful for assaying the presence, amount, activity, or other properties of the biomarker using radioactive imaging (e.g., PET). Such imaging can be used to diagnose disease, monitor disease progression and treatment, and determine the lowest effective dose of therapeutics, and evaluate the effectiveness of therapeutics. For example, the COX-2 protein, which is a biomarker for various diseases described herein, can be assayed using PET imaging of a radiolabeled compound that binds or otherwise interacts with COX-2. However, many existing radiolabeled compounds have a half-life that is impractical for medical use. For example, some radiolabeled COX-2-interacting compounds incorporate an .sup.11C label, which has a half-life of about 20 minutes. It is not practical for such compounds to be sold commercially, used in long-term imaging applications, or transported between medical centers.
[0174] Compounds
[0175] In one aspect, a compound of Formula I
##STR00081##
or a pharmaceutically acceptable salt thereof, is described,
wherein
[0176] A is
##STR00082##
[0177] R is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2; [0178] wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5;
[0179] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of hydrogen, deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, and NHCOR.sup.5; [0180] wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5; and
[0181] each occurrence of R.sup.5 is independently selected from the group consisting of hydrogen, deuterium, .sup.3H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl; [0182] wherein each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, or .sup.131I;
[0183] wherein at least one of R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, or R.sup.5 comprises at least one of .sup.3H, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, or .sup.131I;
[0184] wherein when A is
##STR00083##
R is .sup.11CH.sub.3, R.sup.1 is hydrogen, and R.sup.2 is phenyl, R.sup.4 is not CF.sub.3;
[0185] wherein when A is
##STR00084##
R is CH.sub.3, R.sup.1 and R.sup.2 are hydrogen, and R.sup.3 is CF.sub.3, R.sup.4 is not
##STR00085##
and
[0186] wherein when A is
##STR00086##
R is CH.sub.3, R.sup.1 and R.sup.3 are hydrogen, and R.sup.4 is O.sup.11CH.sub.3, R.sup.2 is not
##STR00087##
[0187] In some embodiments, A is
##STR00088##
In some embodiments, A is
##STR00089##
In some embodiments, A is
##STR00090##
In some embodiments, A is
##STR00091##
[0188] In some embodiments, R is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2. In some embodiments, R is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2. In some embodiments, R is (C.sub.1-C.sub.6)alkyl. In some embodiments, R is aryl. In some embodiments, R is heteroaryl. In some embodiments, R is (C.sub.1-C.sub.6)alkyl-aryl. In some embodiments, R is (C.sub.1-C.sub.6)alkyl-heteroaryl.
[0189] In some embodiments, each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl comprising R is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5. In some embodiments, each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl comprising R is optionally substituted with one or more deuterium, .sup.11C, .sup.18F, or .sup.123I.
[0190] In some embodiments, R is CH.sub.3, .sup.11CH.sub.3, CH.sub.2.sup.18F, (CH.sub.2).sub.2.sup.18F, CF.sub.3, CF.sub.2.sup.18F, CD.sub.2.sup.18F,
##STR00092##
some embodiments, each
##STR00093##
is optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I. In some embodiments, R is CH.sub.3, .sup.11CH.sub.3, or (CH.sub.2).sub.2.sup.18F. In some embodiments, R is CH.sub.3. In some embodiments, R is .sup.1CH.sub.3. In some embodiments, R is (CH.sub.2).sub.2.sup.18F.
[0191] In some embodiments, R.sup.1 is selected from the group consisting of hydrogen, deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, and NHCOR.sup.5. In some embodiments, R.sup.1 is selected from the group consisting of hydrogen, deuterium, halogen, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2. In some embodiments, R.sup.1 is hydrogen, deuterium, .sup.18F, .sup.11C, .sup.123I, (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, or N(R.sup.5).sub.2. In some embodiments, R.sup.1 is hydrogen. In some embodiments, R.sup.1 is (C.sub.1-C.sub.6)alkyl. In some embodiments, R.sup.1 is aryl. In some embodiments, R.sup.1 is heteroaryl. In some embodiments, R.sup.1 is (C.sub.1-C.sub.6)alkyl-aryl. In some embodiments, R.sup.1 is (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, R.sup.1 is N(R.sup.5).sub.2. In some embodiments, R.sup.1 is .sup.18F.
[0192] In some embodiments, each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.1 is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5. In some embodiments, each (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, (C.sub.1-C.sub.6)alkyl-heteroaryl comprising R.sup.1 is optionally substituted with one or more deuterium, .sup.11C, .sup.18F, or .sup.123I.
[0193] In some embodiments, R.sup.1 is hydrogen, deuterium, halogen, .sup.18F, .sup.123I, CH.sub.3, CH.sub.2.sup.18F, (CH.sub.2).sub.2.sup.18F, CF.sub.3, CF.sub.2.sup.18F, CD.sub.2.sup.18F,
##STR00094##
In some embodiments,
##STR00095##
optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I.
[0194] In some embodiments, R.sup.2 is selected from the group consisting of hydrogen, deuterium, .sup.3H, halogen, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, and NHCOR.sup.5. In some embodiments, R.sup.2 is selected from the group consisting of hydrogen, deuterium, halogen, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2. In some embodiments, R.sup.2 is hydrogen, deuterium, .sup.18F, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, or N(R.sup.5).sub.2. In some embodiments, R.sup.2 is hydrogen. In some embodiments, R.sup.2 is (C.sub.1-C.sub.6)alkyl. In some embodiments, R.sup.2 is aryl. In some embodiments, R.sup.2 is phenyl. In some embodiments, R.sup.2 is heteroaryl. In some embodiments, R.sup.2 is (C.sub.1-C.sub.6)alkyl-aryl. In some embodiments, R.sup.2 is (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, R.sup.2 is N(R.sup.5).sub.2.
[0195] In some embodiments, each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.2 is optionally substituted with one or more deuterium, .sup.11C, .sup.3H, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5. In some embodiments, each (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.2 is optionally substituted with one or more deuterium, .sup.11C, .sup.18F, or .sup.123I.
[0196] In some embodiments, R.sup.2 is hydrogen, deuterium, halogen, .sup.18F, .sup.123I, CH.sub.3, .sup.11CH.sub.3, CH.sub.2.sup.18F, (CH.sub.2).sub.2.sup.18F, CF.sub.3, CF.sub.2.sup.18F, CD.sub.2.sup.18F,
##STR00096##
In some embodiments,
##STR00097##
optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I. In some embodiments, R.sup.2 is hydrogen,
##STR00098##
[0197] In some embodiments, R.sup.3 is selected from the group consisting of hydrogen, deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, and NHCOR.sup.5. In some embodiments, R.sup.3 is selected from the group consisting of hydrogen, deuterium, halogen, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2. In some embodiments, R.sup.3 is hydrogen, deuterium, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, or N(R.sup.5).sub.2. In some embodiments, R.sup.3 is hydrogen. In some embodiments, R.sup.3 is (C.sub.1-C.sub.6)alkyl. In some embodiments, R.sup.3 is aryl. In some embodiments, R.sup.3 is heteroaryl. In some embodiments, R.sup.3 is (C.sub.1-C.sub.6)alkyl-aryl. In some embodiments, R.sup.3 is (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, R.sup.3 is N(R.sup.5).sub.2.
[0198] In some embodiments, each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.3 is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5. In some embodiments, each (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.3 is optionally substituted with one or more deuterium, .sup.11C, .sup.18F, or .sup.123I.
[0199] In some embodiments, R.sup.3 is hydrogen, deuterium, halogen, .sup.18F, .sup.123I, CH.sub.3, .sup.11CH.sub.3, CH.sub.2.sup.18F, (CH.sub.2).sub.2.sup.18F, CF.sub.3, CF.sub.2.sup.18F, CD.sub.2.sup.18F,
##STR00099##
In some embodiments,
##STR00100##
are optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I. In some embodiments, R.sup.3 is hydrogen or .sup.18F. In some embodiments, R.sup.3 is hydrogen. In some embodiments, R.sup.3 is .sup.18F.
[0200] In some embodiments, R.sup.4 is selected from the group consisting of hydrogen, deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, and NHCOR.sup.5. In some embodiments, R.sup.4 is selected from the group consisting of hydrogen, deuterium, halogen, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, and N(R.sup.5).sub.2. In some embodiments, R.sup.4 is hydrogen, deuterium, .sup.11C, .sup.18F, .sup.123I, (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, (C.sub.1-C.sub.6)alkyl-heteroaryl, or N(R.sup.5).sub.2. In some embodiments, R.sup.4 is hydrogen. In some embodiments, R.sup.4 is (C.sub.1-C.sub.6)alkyl. In some embodiments, R.sup.4 is aryl. In some embodiments, R.sup.4 is heteroaryl. In some embodiments, R.sup.4 is (C.sub.1-C.sub.6)alkyl-aryl. In some embodiments, R.sup.4 is (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, R.sup.4 is N(R.sup.5).sub.2.
[0201] In some embodiments, each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.4 is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, halogen, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, N(R.sup.5).sub.2, CN, OR.sup.5, SR.sup.5, SOR.sup.5, SO.sub.2R.sup.5, SO.sub.2NHR.sup.5, SO.sub.3R.sup.5, NHSO.sub.2R.sup.5, COR.sup.5, or NHCOR.sup.5. In some embodiments, each (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.4 is optionally substituted with one or more deuterium, .sup.11C, .sup.18F, or .sup.123I.
[0202] In some embodiments, R.sup.4 is hydrogen, deuterium, halogen, .sup.18F, .sup.123I, CH.sub.3, .sup.11CH.sub.3, CH.sub.2.sup.18F, (CH.sub.2).sub.2.sup.18F, CF.sub.3, CF.sub.2.sup.18F, CD.sub.2.sup.18F,
##STR00101##
In some embodiments,
##STR00102##
are optionally substituted with deuterium, .sup.11C, .sup.18F, or .sup.123I. In some embodiments, R.sup.4 is halogen, .sup.18F, CF.sub.2.sup.18F, CF.sub.3,
##STR00103##
In some embodiments, R.sup.4 is CFs, CH.sub.2.sup.18F, CD.sub.2.sup.18F, or CF.sub.2.sup.18F. In some embodiments, R.sup.4 is CFs. In some embodiments, R.sup.4 is CH.sub.2.sup.18F. In some embodiments, R.sup.4 is CD.sub.2.sup.18F. In some embodiments, R.sup.4 is CF.sub.2.sup.18F.
[0203] In some embodiments, each occurrence of R.sup.5 is independently selected from the group consisting of hydrogen, deuterium, .sup.3H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, each occurrence of R.sup.5 is independently selected from the group consisting of hydrogen, deuterium, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, each occurrence of R.sup.5 is independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, R.sup.5 is hydrogen. In some embodiments, R.sup.5 is (C.sub.1-C.sub.6)alkyl. In some embodiments, R.sup.5 is aryl. In some embodiments, R.sup.5 is heteroaryl. In some embodiments, R.sup.5 is (C.sub.1-C.sub.6)alkyl-aryl.
[0204] In some embodiments, each (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)heteroalkenyl, (C.sub.1-C.sub.6)heteroalkynyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.3-C.sub.7)cycloalkenyl, (C.sub.3-C.sub.7)heterocycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)heterocycloalkenyl, aryl, (C.sub.1-C.sub.6)alkyl-aryl, heteroaryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.5 is optionally substituted with one or more deuterium, .sup.3H, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, or .sup.131I. In some embodiments, each (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, (C.sub.1-C.sub.6)alkyl-aryl, and (C.sub.1-C.sub.6)alkyl-heteroaryl of R.sup.5 is optionally substituted with one or more deuterium, .sup.11C, .sup.18F, or .sup.123I.
[0205] In some embodiments, each occurrence of R.sup.5 is independently hydrogen,
##STR00104##
In some embodiments, each occurrence of R.sup.5 is independently hydrogen,
##STR00105##
[0206] In some embodiments, A is
##STR00106##
R is CH.sub.3 or .sup.11CH.sub.3; R.sup.1 and R.sup.3 are hydrogen; R.sup.2 is N(R.sup.5).sub.2; R.sup.4 is F, Cl, CFs, or .sup.18F; and each occurrence of R.sup.5 is independently hydrogen, (C.sub.1-C.sub.6)alkyl-aryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, each occurrence of R.sup.5 is independently hydrogen,
##STR00107##
In some embodiments, R.sup.2 is
##STR00108##
[0207] In some embodiments, A is
##STR00109##
R is .sup.11CH.sub.3; R.sup.1 and R.sup.2 are hydrogen; R.sup.2 is .sup.18F; R.sup.4 is (NR.sup.5).sub.2; and each occurrence of R.sup.5 is independently hydrogen, (C.sub.1-C.sub.6)alkyl-aryl, or (C.sub.1-C.sub.6)alkyl-heteroaryl. In some embodiments, each occurrence of R.sup.5 is independently hydrogen,
##STR00110##
In some embodiments, R.sup.2 is
##STR00111##
[0208] In some embodiments, A is
##STR00112##
R and R.sup.4 are (C.sub.1-C.sub.6)alkyl, optionally substituted with one or more halogen, deuterium, or .sup.18F; R.sup.1 is hydrogen or .sup.18F; and R.sup.2 is aryl, optionally substituted with .sup.18F, or heteroaryl, optionally substituted with .sup.18F. In some embodiments, R is CH.sub.3 or (CH.sub.2).sub.2.sup.18F. In some embodiments, R.sup.2 is
##STR00113##
In some embodiments, R.sup.4 is CF.sub.3, CH.sub.2.sup.18F, CD.sub.2.sup.18F, or CF.sub.2.sup.18F.
[0209] In some embodiments, the compound of Formula I is
##STR00114##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00115##
[0210] In some embodiments, the compound of Formula I is
##STR00116##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00117##
[0211] In some embodiments, the compound of Formula I is
##STR00118##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00119##
[0212] In some embodiments, the compound of Formula I is
##STR00120##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00121##
[0213] In some embodiments, the compound of Formula I is
##STR00122##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00123##
[0214] In some embodiments, the compound of Formula I is
##STR00124##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00125##
[0215] In some embodiments, the compound of Formula I is
##STR00126##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00127##
[0216] In some embodiments, the compound of Formula I is
##STR00128##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00129##
[0217] In some embodiments, the compound of Formula I is
##STR00130##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00131##
[0218] In some embodiments, the compound of Formula I is
##STR00132##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00133##
[0219] In some embodiments, the compound of Formula I is
##STR00134##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00135##
[0220] In some embodiments, the compound of Formula I is
##STR00136##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00137##
[0221] In some embodiments, the compound of Formula I is
##STR00138##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00139##
[0222] In some embodiments, the compound of Formula I is
##STR00140##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00141##
[0223] In some embodiments, the compound of Formula I is
##STR00142##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00143##
[0224] In some embodiments, the compound of Formula I is
##STR00144##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00145##
[0225] In some embodiments, the compound of Formula I is
##STR00146##
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is
##STR00147##
[0226] In some embodiments, the specific activity of the .sup.18F-labelled compounds of Formula I is about 1 to about 5 Ci/μmol. In some embodiments, the molar activity of the .sup.18F-labelled compounds of Formula I is about 0.5 Ci/μmol or greater. In some embodiments, the molar activity of the .sup.18F-labelled compounds of Formula I is about 0.5 to about 2.5 Ci/μmol.
[0227] In some embodiments, the compound of Formula I can exist as a salt form. In some embodiments, the salt form is pharmaceutically acceptable. Non-limiting examples of salts, including pharmaceutically acceptable salts, are those derived from inorganic or organic acids (e.g., hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, and naphthalene-2 sulfonic acids); salts derived from inorganic or organic bases (e.g., sodium, potassium, calcium, magnesium, zinc, ammonia, lysine, arginine, histidine, polyhydroxylated amines, and tetrafluoroborates); and hemi-salts, such as those derived from acids comprising two carboxylic acid groups (e.g., malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid) or diprotic mineral acids (e.g., sulfuric acid). Other exemplary salts are found, for example, in Berge, et al. (J. Pharm. Sci. 1977, 66(1): 1 (incorporated by reference herein in its entirety).
[0228] Processes for Compound Synthesis
[0229] In yet another aspect, a process for synthesizing a compound of Formula I
##STR00148##
[0230] or a pharmaceutically acceptable salt thereof, comprises reacting one or more halogen atom(s) or thioester(s) in the compound with one or more radionuclide source(s) independently selected from the group consisting of deuterium, .sup.3H, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, and .sup.131I.
[0231] In some embodiments, the one or more halogen atom(s) are independently chlorine or bromine. In some embodiments, the one or more halogen atom(s) are chlorine. In some embodiments, the one or more halogen atom(s) are bromine.
[0232] In some embodiments, the one or more thioester(s) comprise
##STR00149##
[0233] In some embodiments, the radionuclide source is a .sup.18F source. In some embodiments, the a .sup.18F source comprises a .sup.18F.sup.− source. Non-limiting examples of .sup.18F.sup.− sources include K.sup.18F and a tetraalkylammonium [.sup.18F]fluoride (e.g., tetrabutylammonium [.sup.18F]fluoride and tetraethylammonium [.sup.18F]fluoride). In some embodiments, the .sup.18F source is K.sup.18F. In some embodiments, the .sup.18F source comprises a [.sup.18F]fluoroalkyl tosylate. A non-limiting example of a [.sup.18F]fluoroalkyl tosylate is 2-[.sup.18F]fluoroethyl tosylate.
[0234] In some embodiments, the process further comprises a chelating agent. In some embodiments, the chelating agent is capable of chelating a cationic metal, such as potassium ion, sodium ion, calcium ion, lithium ion, and the like. In some embodiments, the chelating agent is capable of chelating potassium ion. Non-limiting examples of potassium chelating agents include crown ethers (e.g., 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, and diaza-18-crown-6) and cryptands. In some embodiments, the cryptand is a [2.2.2]cryptand. In some embodiments, the cryptand is Kryptofix® 222 (“K.sub.222”).
[0235] In some embodiments, the process further comprises a base. Non-limiting examples of bases include organic bases, such as tetrabutylammonium hydroxide, pyrrolidine, lithium diisopropylamide, 2,6-lutidine, lithium diethylamide, sodium methoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyl disilazide, potassium tert-butoxide, piperidine, piperazine, sodium acetate, morpholine, diethylamine, tetramethylpiperidine, diisopropylamine, and triethylamine; and inorganic bases, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium hydride, and potassium hydride. In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is tetrabutylammonium hydroxide. In some embodiments, the base is pyrrolidine. In some embodiments, the base is 2,6-lutidine.
[0236] In some embodiments, the process further comprises a polar aprotic solvent. Non-limiting examples of polar aprotic solvents include A. A-dimethylformamide (“DMF”), hexamethylphosphoramide (“HMPA”), dimethyl sulfoxide (“DMSO”), tetramethylene sulfone, 1,4-dioxane, acetone, ether (e.g., diethyl ether, diphenyl ether, and tetrahydrofuran (“THF”)) acetonitrile, methyl ethyl ketone, ethyl acetate, and combinations thereof. In some embodiments, the polar aprotic solvent is THF, DMF, DMSO, or combinations thereof. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the polar aprotic solvent is DMF. In some embodiments, the polar aprotic solvent is DMSO. In some embodiments, the solvent is anhydrous (i.e., comprises less than about 1% water).
[0237] In some embodiments, the radionuclide source is a .sup.11C source. In some embodiments, the .sup.11C source comprises a [.sup.11C]alkyl halide and a [.sup.11C]alkyl triflate. A non-limiting example of a [.sup.11C]alkyl halide is .sup.11CH.sub.3I. A non-limiting example of a [.sup.11C]alkyl triflate is .sup.11CH.sub.3OTf. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I. In some embodiments, the .sup.11C source is .sup.11CH.sub.3OTf.
[0238] In some embodiments, the process further comprises an oxidant. In some embodiments, the process further comprises an oxidant when the radionuclide source is a .sup.11C source. Non-limiting examples of oxidants include Oxone®, optionally with a water/THF solvent, a peroxyacid (e.g., meta-chloroperoxybenzoic acid), potassium peroxymonosulfate, H.sub.2O.sub.2, NaIO.sub.4, t-BuOCl, Ca(OCl).sub.2, NaClO.sub.2, NaOCl, a dioxirane, and KMnO.sub.4. In some embodiments, the oxidant is Oxone® or potassium peroxymonosulfate. In some embodiments, the oxidant is Oxone®.
[0239] In some embodiments, the process comprises reacting one or more chlorine or bromine atom(s) in a compound of Formula I with a .sup.18F source. In some embodiments, the .sup.18F source is K.sup.18F. In some embodiments, the .sup.18F source is 2-[.sup.18F]fluoroethyl tosylate.
[0240] In some embodiments, the process comprises reacting one or more thioester(s) in a compound of Formula I with a .sup.11C source in the presence of an oxidant. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I. In some embodiments, the .sup.11C source is .sup.11CH.sub.3OTf. In some embodiments, the oxidant is Oxone®.
[0241] In some embodiments, the compound of Formula I is
##STR00150##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00151##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00152##
and the process comprises reacting the compound
##STR00153##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0242] In some embodiments, the compound of Formula I is
##STR00154##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00155##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00156##
and the process comprises reacting the compound
##STR00157##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0243] In some embodiments, the compound of Formula I is
##STR00158##
a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00159##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00160##
and the process comprises reacting the compound
##STR00161##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0244] In some embodiments, the compound of Formula I is
##STR00162##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00163##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00164##
and the process comprises reacting the compound
##STR00165##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0245] In some embodiments, the compound of Formula I is
##STR00166##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00167##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00168##
and the process comprises reacting the compound
##STR00169##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0246] In some embodiments, the compound of Formula I is
##STR00170##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00171##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00172##
and the process comprises reacting the compound
##STR00173##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0247] In some embodiments, the compound of Formula I is
##STR00174##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00175##
with a .sup.11C source and an oxidant. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I and/or .sup.11CH.sub.3OTf and the oxidant is Oxone®. In some embodiments, the compound of Formula I is
##STR00176##
and the process comprises reacting the compound
##STR00177##
with a .sup.11C source and an oxidant. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I and/or .sup.11CH.sub.3OTf and the oxidant is Oxone®.
[0248] In some embodiments, the compound of Formula I is
##STR00178##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00179##
with a .sup.11C source and an oxidant. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I and/or .sup.11CH.sub.3OTf and the oxidant is Oxone®. In some embodiments, the compound of Formula I is
##STR00180##
and the process comprises reacting the compound
##STR00181##
with a .sup.11C source and an oxidant. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I and/or .sup.11CH.sub.3OTf and the oxidant is Oxone®.
[0249] In some embodiments, the compound of Formula I is
##STR00182##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00183##
with a .sup.11C source and an oxidant. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I and/or .sup.11CH.sub.3OTf and the oxidant is Oxone®. In some embodiments, the compound of Formula I is
##STR00184##
and the process comprises reacting the compound
##STR00185##
with a .sup.11C source and an oxidant. In some embodiments, the .sup.11C source is .sup.11CH.sub.3I and/or .sup.11CH.sub.3OTf and the oxidant is Oxone®.
[0250] In some embodiments, the compound of Formula I is
##STR00186##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00187##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00188##
and the process comprises reacting the compound
##STR00189##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0251] In some embodiments, the compound of Formula I is
##STR00190##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00191##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00192##
and the process comprises reacting the compound
##STR00193##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0252] In some embodiments, the compound of Formula I is
##STR00194##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00195##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source. In some embodiments, the compound of Formula I is
##STR00196##
and the process comprises reacting the compound
##STR00197##
with a .sup.18F source. In some embodiments, the .sup.18F source is a .sup.18F.sup.− source.
[0253] In some embodiments, the compound of Formula I is
##STR00198##
or a pharmaceutically acceptable salt thereof; and the process comprises reacting the compound
##STR00199##
with a .sup.18F source. In some embodiments, the .sup.18F source is 2-[.sup.18F]fluoroethyl tosylate. In some embodiments, the compound of Formula I is
##STR00200##
and the process comprises reacting the compound
##STR00201##
with a .sup.18F source. In some embodiments, the .sup.18F source is 2-[.sup.18F]fluoroethyl tosylate.
[0254] In some embodiments, compounds of Formula I may be synthesized according to Scheme 1.
##STR00202##
[0255] In some embodiments, the base is an alkoxide (e.g., NaOCH.sub.3). In some embodiments, the solvent is a polar protic solvent (e.g., water, methanol, ethanol, isopropanol, and t-butanol). In some embodiments, [Cl] is a chlorinating agent (e.g., POCl.sub.3). In some embodiments, [O] is an oxidizing agent. Non-limiting examples of oxidizing agents include Oxone®, optionally with a water/THF solvent, a peroxyacid (e.g., meto-chloroperoxybenzoic acid), potassium peroxymonosulfate, H.sub.2O.sub.2, NaIO.sub.4, t-BuOCl, Ca(OCl).sub.2, NaClO.sub.2, NaOCl, a dioxirane, and KMnO.sub.4. In some embodiments, the oxidizing agent is Oxone® or potassium peroxymonosulfate. In some embodiments, the chloride is displaced with R.sup.2 using, for example, a cross-coupling reaction (e.g., a palladium-mediated cross-coupling reaction) or a substitution reaction (e.g., a nucleophilic aromatic substitution reaction).
[0256] Additional processes, reagents, and conditions for synthesis of compounds of Formula I can be found in U.S. Patent Application Publication No. 2008/0138282 A1 (incorporated herein by reference in its entirety).
[0257] In some embodiments, the radiochemical yield of the reaction to install the .sup.18F radioisotope in compounds of Formula I is about 10 to about 50%. In some embodiments, the radiochemical yield of the reaction to install the .sup.18F radioisotope in compounds of Formula I is about 15 to about 35%. In some embodiments, the radiochemical yield of the reaction to install the .sup.18F radioisotope in compounds of Formula I is about 20 to about 30%.
[0258] Methods of Radio Imaging
[0259] In yet another aspect, a method for imaging a sample or organism comprises:
[0260] (a) administering to the sample or organism a compound of Formula I
##STR00203##
[0261] or a pharmaceutically acceptable salt thereof, in an amount effective to detect emission of deuterium, .sup.3H, .sup.11C, .sup.18F, .sup.75Br, .sup.76Br, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, or a combination thereof; and
[0262] (b) measuring the emission of the one or more radionuclide(s) in the compound.
[0263] In some embodiments, the amount effective to detect emission is the weight, concentration, or molar activity of the compound, or a pharmaceutically acceptable salt or dosage form thereof, that, when dosed to the sample or organism, permits detection of the radioactive emission of the radioisotope(s). In some embodiments, this is an amount that permits detection of the radioactive emission of the radioisotope(s) via PET. In some embodiments, this is an amount that permits detection of the radioactive emission of .sup.18F. A non-limiting example of an imaging-effective dosage amount ranges from about 0.001 mCi to about 30 mCi.
[0264] In some embodiments, the emission is measured using PET.
[0265] In some embodiments, the sample is a cell culture. Non-limiting examples of cell cultures include BxPC3 (COX-2-positive) and PANC-1 (COX-2-negative).
[0266] In some embodiments, the organism is an animal. In some embodiments, the organism is a mammal. In some embodiments, the mammal is a mouse, rat, pig, dog, monkey, baboon, or human. In some embodiments, the mammal is a mouse. In some embodiments, the mammal is a rat. In some embodiments, the mammal is a pig. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a monkey. In some embodiments, the monkey is a rhesus macaque. In some embodiments, the mammal is a baboon. In some embodiments, the mammal is a human.
[0267] In some embodiments, the compound can be administered to the sample or organism per se (neat) or in the form of a pharmaceutically acceptable salt or solution. For example the salt or solution may be administered by intravenous, intramuscular, or other parenteral means. The compound, salt, or solution can also be administered by intranasal application, inhalation, topically, orally, rectally, vaginally, or as implants. Suitable liquid or solid forms include, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes or other vesicles, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin, granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with protracted release of active compounds in whose preparation excipients and additives and/or auxiliaries include, for example, disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. In some embodiments, the compound can be administered as a controlled- or sustained-release form. In some embodiments, the compound can be administered in pro-drug form. Additional administration forms and modes of administration are known in the art of pharmacy. See generally, Remington, The Science and Practice of Pharmacy, Vols. 1 and 2, Pharmaceutical Press 2013 (incorporated herein by reference in its entirety). See also U.S. Patent Application Publication No. 2008/0138282 A1 (incorporated herein by reference in its entirety).
[0268] In some embodiments, the compound interacts with a biological target and measuring the emission allows determination of the expression level or distribution of the biological target in the sample or organism. In some embodiments, the biological target (e.g., protein) is implicated in a disease (e.g., is downregulated or upregulated, is under-expressed or overexpressed, etc.) and measuring the emission allows diagnosis, progression, and treatment of the disease to be assessed. In some embodiments, the compound interacts with a protein and measuring the emission allows determination of the expression level or distribution of the protein in the sample or organism. In some embodiments, the protein is involved in inflammation and measuring the emission allows determination of the amount or distribution of inflammation, inflection, and/or injury in the sample or organism. In some embodiments, the protein is COX-2. In some embodiments, the compound interacts with (e.g., binds) and/or inhibits COX-2. In some embodiments, this binding or inhibition, in combination with the imaging method, is used to determine COX-2 expression level or activity, or diagnose or monitor a disease or treatment involving COX-2.
[0269] In some embodiments, the animal is known or suspected to have a condition or state selected from the group consisting of arthritis (e.g., rheumatoid arthritis, osteoarthritis, and spondyloarthropathies), cardiovascular disease (e.g., atherosclerosis, myocardial infarction, myocardial ischemia, periarteritis nodosa, and vascular disease), central nervous system damage (e.g., from stroke, ischemia, and trauma), central nervous system disorder (e.g., multiple sclerosis, a seizure disorder, such as epilepsy, headache, including but not limited to migraine headache, and brain injury, including but not limited to traumatic brain injury), gastrointestinal disorder (e.g., irritable bowel syndrome), hypersensitivity (e.g., autoimmune disease, including but not limited to aplastic anemia, graft rejection, lupus, scleroderma, and allergy, including but not limited to allergic rhinitis), inflammatory disease (e.g., asthma, Bechet's disease, bronchitis, bursitis, Crohn's disease, endotoxin shock syndrome, gastritis, gingivitis, inflammatory bowel disease, polymyositis, pulmonary inflammation, such as acute respiratory disease syndrome and severe acute respiratory syndrome from viral (e.g., COVID-19) and bacterial infections, Lyme disease, meningitis, and from cystic fibrosis, rheumatic fever, sarcoidosis, tendinitis, thyroiditis, and ulcerative colitis), metabolic disorder (e.g., affecting bone metabolism, type 1 diabetes, and type 2 diabetes), neoplastic disease (e.g., cancer, including but not limited to colorectal cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, cervical cancer, skin cancer, and lymphoma, including but not limited to Hodgkin lymphoma and non-Hodgkin lymphoma), neurodegenerative disease (e.g., multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, cortical dementias, Huntington's disease, and Parkinson's disease), neuromuscular junction disease (e.g., myasthenia gravis), ophthalmic disease (e.g., retinitis, retinopathies, uveitis, ocular photophobia, conjunctivitis, and acute injury to the eye tissue), post-operative inflammation (e.g., from ophthalmic surgery, cataract surgery, and refractive surgery), psychiatric condition (e.g., depressive disorder, schizophrenia, and an alcohol use disorder), reproductive event (e.g., ovulation, pregnancy, and child birth), respiratory disease (e.g., respiratory distress syndrome), skin disorder (e.g., psoriasis, eczema, burns, and dermatitis), tissue repair, urogenital disease (e.g., renal disease, including but not limited to nephritis and nephrotic syndrome), white matter disease, and a combination thereof.
[0270] In some embodiments, the condition is Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, myocardial infarction, traumatic brain injury, inflammatory disease, cancer, renal disease, or amyotrophic lateral sclerosis.
[0271] In some embodiments, the animal is known or suspected to be experiencing pain. In some embodiments, the animal is known or suspected to be experiencing pain as a result of the conditions listed above.
[0272] In some embodiments, COX-2 is induced by inflammatory stimuli. In some embodiments, COX-2 catalyzes prostanoid formation associated with, for example, inflammation and proliferative diseases. In some embodiments, COX-2 is modestly expressed under normal physiologic conditions and plays a role in, for example, brain, cardiac, and kidney function, but is upregulated or overexpressed during inflammation. In some embodiments, excessive inflammation and associated COX-2 induction may be part of the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as in traumatic brain injury. In some embodiments, COX-2 induction is involved in pain, major depressive disorder, schizophrenia, arthritis, cancer, and acute allograft rejection. In some embodiments, inhibition of COX-2 may be a protective treatment strategy by slowing or halting the progression of disease. In some embodiments, monitoring in vivo changes in COX-2 expression can be used for quantifying disease pathogenesis, such as detecting organ rejection, detecting arthritic joints, and assessing target occupancy and biological effects of COX-2 inhibitors. In some embodiments, noninvasive radio imaging, such as PET, is useful for assessing brain diseases due to the difficulty of accessing the brain.
[0273] In some embodiments, the method can be used to measure and/or detect COX-2 protein in COX-2 associated diseases, conditions, and disorders. Non-limiting examples of COX-2-associated diseases, conditions, and disorders include a condition or state selected from the group consisting of arthritis (e.g., rheumatoid arthritis, osteoarthritis, and spondyloarthropathies), cardiovascular disease (e.g., atherosclerosis, myocardial infarction, myocardial ischemia, periarteritis nodosa, and vascular disease), central nervous system damage (e.g., from stroke, ischemia, and trauma), central nervous system disorder (e.g., multiple sclerosis, a seizure disorder, such as epilepsy, headache, including but not limited to migraine headache, and brain injury, including but not limited to traumatic brain injury), gastrointestinal disorder (e.g., irritable bowel syndrome), hypersensitivity (e.g., autoimmune disease, including but not limited to aplastic anemia, graft rejection, lupus, scleroderma, and allergy, including but not limited to allergic rhinitis), inflammatory disease (e.g., asthma, Bechet's disease, bronchitis, bursitis, Crohn's disease, endotoxin shock syndrome, gastritis, gingivitis, inflammatory bowel disease, polymyositis, pulmonary inflammation, such as acute respiratory disease syndrome and severe acute respiratory syndrome from viral (e.g., COVID-19) and bacterial infections, Lyme disease, meningitis, and from cystic fibrosis, rheumatic fever, sarcoidosis, tendinitis, thyroiditis, and ulcerative colitis), metabolic disorder (e.g., affecting bone metabolism, type 1 diabetes, and type 2 diabetes), neoplastic disease (e.g., cancer, including but not limited to colorectal cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, cervical cancer, skin cancer, and lymphoma, including but not limited to Hodgkin lymphoma and non-Hodgkin lymphoma), neurodegenerative disease (e.g., multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, cortical dementias, Huntington's disease, and Parkinson's disease), neuromuscular junction disease (e.g., myasthenia gravis), ophthalmic disease (e.g., retinitis, retinopathies, uveitis, ocular photophobia, conjunctivitis, and acute injury to the eye tissue), post-operative inflammation (e.g., from ophthalmic surgery, cataract surgery, and refractive surgery), psychiatric condition (e.g., depressive disorder, alcohol use disorder, and schizophrenia, reproductive event (e.g., ovulation, pregnancy, and child birth), respiratory disease (e.g., respiratory distress syndrome), skin disorder (e.g., psoriasis, eczema, burns, and dermatitis), tissue repair, urogenital disease (e.g., renal disease, including but not limited to nephritis and nephrotic syndrome), white matter disease, or a combination thereof. In some embodiments, the condition is Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, myocardial infarction, traumatic brain injury, inflammatory disease, cancer, renal disease, or amyotrophic lateral sclerosis.
[0274] In some embodiments, the method can be used to detect or monitor processes, diseases, or disorders that may involve the upregulation of COX-2 protein expression including, but not limited to upregulation and/or overexpression of COX-2 is associated with inflammation, pain, fever, arthritis (e.g., rheumatoid arthritis and osteoarthritis), neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), angiogenesis, cancer, stroke, cardiac condition (e.g., myocardial infarction and atherosclerosis), diabetes, allograft rejection, urogenital disease, renal function, tissue repair, bone metabolism, ovulation, pregnancy, and child birth.
[0275] In some embodiments, the method can be used to screen a sample or organism for diseases, disorders, states, or conditions that are related to COX-2 expression or activity. Non-limiting examples include inflammation, pain, fever, arthritis (e.g., rheumatoid arthritis and osteoarthritis), neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), vascular condition (e.g., angiogenesis), cancer, reproduction (e.g., ovulation, pregnancy, and child birth), renal function, tissue repair, bone metabolism, stroke, cardiac condition (e.g., myocardial infarction, atherosclerosis), diabetes, allograft rejection, and urogenital disease.
[0276] In some embodiments, the method can be used to screen for organisms that are more susceptible to side effects of COX-2 inhibitors, as manifested by an increased detection of the compounds of Formula I in specified tissue compartments.
[0277] In some embodiments, the method can be used to determine the efficacy of COX-2 inhibitors administered to an organism to treat a disorder that involves the upregulation of COX-2 protein expression.
[0278] In some embodiments, the method can be used to monitor the course of inflammation in an organism. For example, whether a particular COX-2 inhibitor therapeutic regimen aimed at ameliorating the cause of the inflammatory process, or the inflammatory process itself, is effective, can be determined by measuring the decrease of COX-2 protein expression at suspected sites of inflammation.
[0279] Additional uses for the methods described herein can be found in U.S. Patent Application Publication No. 2008/0138282 A1 (incorporated herein by reference in its entirety).
[0280] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification, and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
EXAMPLES
Example 1: Radiosynthesis and Evaluation of [.SUP.18.F]FMTP and [.SUP.18.F]FMPP
[0281] COX, or prostaglandin endoperoxidase synthase, is an enzyme involved in the biosynthesis of prostaglandins, prostacyclins, and thromboxanes from arachidonic acid. Among the three known isoforms of COX (COX-1, COX-2, and COX-3), COX-1 has predominantly constitutive activity and is involved in many normal physiological functions. In contrast, COX-2 is inducible under normal physiologic conditions, with relatively low constitutive activity and mostly found in kidney, brain, and heart. The third isoform, COX-3, may be responsible for febrile response and mediates the antipyretic effects of aspirin and acetaminophen. COX-2 inhibition mediates the analgesic activities of NSAIDs. COX-2, induced by inflammatory stimuli, catalyzes prostanoid formation associated with inflammation and proliferative diseases, including those in the CNS. Neuroinflammation and COX-2 induction are implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and ALS, as well as psychiatric disorders, smoking, seizure disorders, and brain injuries (e.g., TBI). COX-2 induction is also involved in for example, pain, arthritis, cancers, myocardial infarction, and acute allograft rejection. COXIBs can have anti-inflammatory effects.
[0282] Upregulation/overexpression of COX-2 is involved in neuroinflammation associated with many neurological diseases and malignancies of the brain. Outside the brain, inflammation and COX-2 induction contribute to the pathogenesis of, for example, pain, arthritis, and acute allograft rejection, and to responses to, for example, infections, tumors, autoimmune disorders, and injuries. Therefore, targeting COX-2 may be a potential neuroprotective treatment strategy aiming to reduce the progression of neurodegenerative and other diseases.
[0283] Monitoring in vivo changes in COX-2 expression allows, for example, quantification of inflammation, tracking of disease course, assessing target occupancy of NS AIDs, and or monitoring clinical use of FDA-approved COXIB medications. Prior methods of COX-2 quantification include ex vivo assays of tissue samples, invasively obtained from biopsies. PET imaging would allow noninvasive and in vivo visualization of COX-2 throughout the body. Prior COX-2 PET ligands were not successful for in vivo quantification of COX-2 due to limitations, such as suboptimal COX-2 affinity, high nonspecific binding, de[.sup.18F]fluorination, skeletal uptake, poor brain or organ uptake, inability to detect basal or low level of COX-2, and poor signal-to-noise ratio due to lipophilicity. [.sup.11C]TMI, a potent COX-2 inhibitor, was the only prior radiotracer exhibiting partial blocking of constitutive COX-2 level in baboon brain, however, its ability to image inflammation in animal disease models was yet to be proven. [.sup.18F]Pyricoxib, another prior COX-2 inhibitor belonging to the class of 2-(4-methylsulfonylphenyl)pyrimidines, and the prior triazole analogue [.sup.18F]triacoxib, showed a higher binding in COX-2 positive cells (HCA-7) compared with COX-2 negative cells (HCT-116). However, both tracers demonstrated only modest binding in xenografts in vivo and did not show significant uptake in brain. See
[0284] Materials and Methods
[0285] The radiochemical synthesis of [.sup.18F]FMTP and [.sup.18F]FMPP were optimized using a chlorine-to-fluorine displacement method, by reacting .sup.18F-fluoride/K222/K.sub.2CO.sub.3 with the corresponding chlorine precursor molecules. Cellular uptake studies of [.sup.18F]FMTP were performed in COX-2-positive BxPC3 and COX-2-negative PANC-1 cell lines with unlabeled FMTP as well as celecoxib (5 μM) to define specific binding agents. Dynamic microPET image acquisition was performed in anesthetized nude mice, LPS-induced neuroinflammation mice, and PBS-administered control mice using a Trifoil mPET/CT for a scan period of 50 or 60 minutes.
[0286] Materials
[0287] .sup.18F was produced using Eclipse cyclotron (Siemens, Knoxville, Tenn.). Gamma-ray detector (Bioscan Flow-Count fitted with NaI detector) coupled in series with a UV detector (Waters Model 996 set at 254 nm) were used for detection of radiolabeled products. Data acquisition for both the analytical and preparative systems was accomplished using a Waters Empower Chromatography System. Dynamic microPET image acquisitions were performed with Trifoil mPET/CT scanner.
[0288] Synthesis of [.sup.18F]FMTP and [.sup.18F]FMPP
##STR00204##
[0289] Synthesis of the starting 4-(methylthio)benzimidamide was conducted as reported in Orjales et al. “Novel 2-(4-Methylsulfonylphenyl)pyrimidine Derivatives as Highly Potent and Specific COX-2 Inhibitors. Bioorg. Med. Chem. 2008, 16:2183-99 (incorporated herein by reference in its entirety. See also Scheme 1.
[0290] Thiophene-2-ylmethanamine (68 mg, 0.6 mmol) was added to a solution of 4,6-dichloro-2-(4-(methylsulfonyl)phenyl)pyrimidine (0.3 mmol, 90 mg) in 4 mL dry dichloromethane and 0.1 mL triethylamine. The reaction mixture was stirred at room temperature for 1 hour and, at this time, HPLC analyses showed >95% consumption of the chloro-substrate. The reaction mixture was evaporated and chromatographed over silica gel using 40:60 ethyl acetate-hexane to afford 75 mg (65%) of Cl-MTP as pale-yellow solid. Cl-MTP: melting point: 169-171° C.; .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.0 (3H, s, CH.sub.3), 4.85 (2H, bs, CH.sub.2), 5.3 (1H, bs, NH), 6.3 (1H, s), 6.9 (1H, m), 7.0 (1H, d, J=2.81 Hz), 7.2 (2H, d, overlapped with CDCl.sub.3), 7.9 (2H, d, J=8.53 Hz), and 8.5 (2H, d, J=8.56 Hz).
[0291] Tetra-n-butylammonium fluoride (“TBAF”) (0.1 mL, 1 M solution in THF) was added to a solution of Cl-MTP (20 mg, 0.05 mmol) in DMF (2 mL). The resulting solution was heated at 140° C. for 1 hour, at which time point, HPLC analyses showed >95% consumption of Cl-MTP. The reaction mixture was then allowed to cool, diluted with water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined ethyl acetate fractions were further washed with saturated brine, dried over anhydrous MgSO.sub.4, and chromatographed over silica gel (20% ethyl acetate-hexane) to afford 15 mg (85%) of FMTP as pale-yellow solid. FMTP: melting point: 131.5° C.; .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.0 (3H, s, CH.sub.3), 4.8 (2H, bs, CH.sub.2), 5.9 (1H, bs, NH), 6.4 (1H, s), 6.9-7 (1H, m), 7.05 (1H, d, J=2.82 Hz), 7.2 (2H, d, overlapped with CDCl.sub.3), 8.0 (2H, d, J=8.51), 8.6 (2H, d, J=8.54); HRMS (MH+) calculated for: C.sub.16H.sub.15FN.sub.3O.sub.2S.sub.2: 364.0512; Found: 364.0533.
##STR00205##
[0292] Benzylamine (64 mg, 0.6 mmol) was added to a solution of 4,6-dichloro-2-(4-(methylsulfonyl)phenyl)pyrimidine (0.3 mmol, 90 mg) in 4 mL dry di chloromethane and 0.1 mL triethylamine. The reaction mixture was stirred at room temperature for 1 hour and, at this time, HPLC analyses showed >95% consumption of the chloro-substrate. The reaction mixture was evaporated and chromatographed over silica gel using 40:60 ethyl acetate-hexane to afford 65 mg (60%) of Cl-MPP as pale-yellow solid.
[0293] TBAF (0.1 mL, 1 M solution in THF) was added to a solution of Cl-MPP (20 mg, 0.05 mmol) in DMF (2 mL). The resulting solution was heated at 140° C. for 1 hour, at which time point, HPLC analyses showed >95% consumption of Cl-MTP. The reaction mixture was then allowed to cool, diluted with water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined ethyl acetate fractions were further washed with saturated brine, dried over anhydrous MgSO.sub.4, and chromatographed over silica gel (20% ethyl acetate-hexane) to afford 13 mg (80%) of FMPP as pale-yellow solid. FMPP: melting point: 125.5° C.; .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.0 (3H, s, CH.sub.3), 4.9 (2H, bs, CH.sub.2), 6.1 (1H, bs, NH), 6.5 (1H, s), 7.3 (5H, m), 8.0 (2H, d, J=8.51), 8.6 (2H, d, J=8.54); HRMS (MH+) calculated for: C.sub.18H.sub.17FN.sub.3O.sub.2S: 357.0942; Found: 357.0926.
[0294] .sup.18F (Eclipse cyclotron, Siemens) trapped from QMA was eluted with 1 mL of 10:1 acetonitrile:water, containing K.sub.222 (36 mg) and potassium carbonate (2 mg). The reaction mixture was azeotropically heated and dried at 98° C. under a stream of argon by the repeated addition of acetonitrile (4×0.5 mL). A solution of approximately 2 mg of Cl-MTP or Cl-MPP in 500 μL of DMSO was then added to the reaction vial, sealed, and heated for 20 minutes at 140° C. The reaction mixture was allowed to cool to room temperature, diluted with 20 mL water, and passed through a classic C-18 Sep-Pak cartridge and eluted with 1 mL acetonitrile. The crude product in acetonitrile was injected onto a semipreparative HPLC column (Phenomenex, Prodigy ODS-Prep 10×250 mm, 10 μm; and eluted with 50:50 acetonitrile:0.1 M ammonium formate with a flow rate of 8 mL/min). [.sup.18F]FMTP eluted at 9-10 minutes and [.sup.18F]FMPP eluted at 12 minutes, and were collected based on the γ-detector reading, diluted with 50 mL of deionized water and passed through a classic C-18 Sep-Pak cartridge, washed with 10 mL of deionized water, and eluted with 1 mL of ethanol. Reconstruction of the product in 1 mL of absolute ethanol afforded [.sup.18F]FMTP in 35±5% yield and [.sup.18F]FMPP at 30±5% at the end of synthesis (“EOS”). A portion of the ethanol solution was analyzed by analytical HPLC (Phenomenex, Prodigy ODS(3) 4.6×250 mm, 5 μm; mobile phase; 60:40 acetonitrile:0.1 M AMF, flow rate 2 mL/min, tR=˜5-6 minutes) to determine the molar activity, chemical, and radiochemical purities. The ethanol solution was then diluted to a volume of 10 mL with saline and filtered through a sterile environment, and a portion of this solution was formulated for injection.
[0295] In Vitro and In Vivo Evaluation of [.sup.18F]FMTP
[0296] Cell Update of [.sup.18F]FMTP
[0297] BxPC3 and PANC-1 human pancreas carcinoma cell lines were plated on a 24-well plate at 2×10.sup.5 cells/well. After 48 hours, [.sup.18F]FMTP was added (2.0 μCi/mL) to the cell medium for 30 minutes. For blocking experiments, non-labelled FMTP or celecoxib (5 μM) was added to cells 30 minutes before [.sup.18F]FMTP. After incubation with [.sup.18F]FMTP, cells were washed 4 times with cold PBS, lysed with 0.1 N NaOH, and counted in a gamma counter (Hidex AMG, LabLogic, Tampa, Fla.).
[0298] Proof-of-concept and selectivity of [.sup.18F]FMTP binding to COX-2 was examined by evaluating the tracer uptake in COX-2-positive BxPC3 and a control COX-2-negative PANC1 human pancreatic carcinoma cell lines.
[0299] MicroPET Imaging of [.sup.18F]FMTP
[0300] Animals (male white mice) were anesthetized with isoflurane (l %-2% isoflurane in 100% oxygen) using a nose cone, and a 29-gauge needle connected to a catheter was placed into the lateral tail vein. For neuroinflammation, mice were stereotactically injected with 5 μg of LPS or PBS (controls) in the brain and imaging experiments conducted 24 hours later. The animal was placed in prone position on the platform of the scanner and moved into the center of the field of view guided by laser beam calibration. Immediately after scan start, [.sup.18F]FMTP (˜2.5 MBq 25 mL in 20% ethanol-saline solution) was injected through the tail-vein catheter manually. The error caused by the injector and catheter was corrected by subtracting the remaining dose. 40-minute dynamic imaging was acquired on a microPET scanner (Siemens Inveon). The acquired list-mode data were reconstructed with 3D ordered subset expectation maximization (OSEM) algorithm using the software of Siemens Inveon Acquisition Workplace with a framing protocol of 2×30 seconds, 4×60 seconds, 3×120 seconds, 3×180 seconds, and 4×300 seconds. Using PMOD software (version 4.0, Switzerland), three-dimensional ellipsoid volume of interests (“VOIs”) ranging from 2-to-6 mm were placed manually at the center of the brain, heart (blood-pool), liver, proximal humerus (bone), and posterior cervical muscle. The standardized uptake values (“SUVs”) were estimated using a calibration factor calculated from the phantom study and time activity curves (“TACs”) were derived from VOIs in the series of reconstructed images.
[0301]
[0302] A new method for radiosynthesis of [.sup.18F]FMTP and [.sup.18F]FMPP included a chlorine-to-.sup.18F displacement reaction of aryl[1,3]pyrimidine core molecule. Advantages of the radiosynthesis described in one or more embodiments herein include, but are not limited to, accessibility of precursor, one step, no prosthetic group required, facile separation and purification, and no de[.sup.18F]fluorination. Proof-of-concept of the use of [.sup.18F]FMTP for quantifying COX-2 was demonstrated first, in vitro, in COX-2-positive BxPC3 cells. MicroPET imaging of normal mice demonstrated BBB penetration and a fast washout of radioactivity from brain, possibly due to low concentration of COX-2 in normal brain. [.sup.18F]FMTP showed a higher binding in LPS-induced neuroinflammation compared to binding in the brain of control mice. Specific binding to COX-2 in cell lines, lack of in vivo de[.sup.18F]fluorination and skeletal uptake, BBB permeability, and higher brain binding in neuroinflammation demonstrated the potential of [.sup.18F]FMTP as a PET tracer for imaging inflammation where COX-2 overexpression is reported. [.sup.18F]FMTP may be useful for rapid determination of the lowest effective dose of, e.g., a COXIB.
REFERENCES
[0303] Fitzpatrick F. “Cyclooxygenase enzymes: regulation and function. Curr. Pharm. Des. 2004, 10(6):577-88 (incorporated herein by reference in its entirety). [0304] DeWitt D L. “Prostaglandin endoperoxide synthase: regulation of enzyme expression.” Biochim. Biophys. Acta. 1991, 1083(2): 121-34 (incorporated herein by reference in its entirety). [0305] Smith W L et al. “Prostaglandin endoperoxide synthase: structure and catalysis.” Biochim. Biophys. Acta. 1991, 1083(1): 1-17 (incorporated herein by reference in its entirety). [0306] Kumata K et al. “Assessment of radioligands for PET imaging of cyclooxygenase-2 in an ischemic neuronal Injury model.” Brain Res. 2013, 1533:152-62 (incorporated herein by reference in its entirety). [0307] Yasojima K et al. “Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs.” Brain Res. 1999, 830(2):226-36 (incorporated herein by reference in its entirety). [0308] Ho L et al. “Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease.” J Neurosci. Res. 1999, 57(3):295-303 (incorporated herein by reference in its entirety). [0309] Dotting R et al. “COX-3 and the mechanism of action of paracetamol/acetaminophen.” Prostaglandins Leukot Essent Fatty Acids 2005, 72(2): 85-7 (incorporated herein by reference in its entirety). [0310] Schwab J M et al. “COX-3 the enzyme and the concept: steps towards highly specialized pathways and precision therapeutics?” Prostaglandins Leukot Essent Fatty Acids 2003, 69(5):339-43 (incorporated herein by reference in its entirety). [0311] Warner T D et al. “Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum?” Proc. Nad. Acad. Sci. USA 2002, 99(21): 13371-3 (incorporated herein by reference in its entirety). [0312] Choi S H et al. “The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research.” Trends Pharmacol Sci. 2009, 30(4): 174-81 (incorporated herein by reference in its entirety). [0313] Minghetti L. “Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases.” J. Neuropathol. Exp. Neurol. 2004, 63(9):901-10 (incorporated herein by reference in its entirety). [0314] Guan P P et al. “Integrated communications between cyclooxygenase-2 and Alzheimer's disease.” FASEB J. 2019, 33(1): 13-33 (incorporated herein by reference in its entirety). [0315] Dhir A. “An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders.” Expert Opin. Investig. Drugs. 2019, 28(2): 191-205 (incorporated herein by reference in its entirety). [0316] Rojas A et al. “The COX-2/prostanoid signaling cascades in seizure disorders.” Expert Opin. Ther. Targets. 2019, 23(1): 1-13 (incorporated herein by reference in its entirety). [0317] Strauss K I. “COX2 inhibitors for acquired brain injuries: Is the time ripe?” Crit. Care. Med. 2010, 38(2):723-724 (incorporated herein by reference in its entirety). [0318] de Vries E F et al. “Nuclear imaging of inflammation in neurologic and psychiatric disorders.” Curr. Clin. Pharmacol. 2006, 1(3):229-42 (incorporated herein by reference in its entirety). [0319] Fond G et al. “Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review.” Acta. Psychiatr. Scand. 2014, 129(3): 163-79 (incorporated herein by reference in its entirety). [0320] Na K S et al. “The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia.” Prog. Neuropsychopharmacol. Biol. Psychiatry. 2014, 48:277-86 (incorporated herein by reference in its entirety). [0321] Mathew S T et al. “Efficacy and safety of COX-2 inhibitors in the clinical management of arthritis: mini review” ISRN Pharmacol. 2011, 2011:480291 (incorporated herein by reference in its entirety). [0322] Yang X et al. “Upregulation of COX-2 during cardiac allograft rejection.” Circulation 2000, 101(4):430-8 (incorporated herein by reference in its entirety). [0323] Patti R et al. “Overexpression of cyclooxygenase-2 (COX-2) in human primitive neuroectodermal tumors: effect of celecoxib and rofecoxib.” Cancer Lett. 2002, 180(1): 13-21 (incorporated herein by reference in its entirety). [0324] Puljak L et al. “Celecoxib for osteoarthritis.” Cochrane Database Syst. Rev. 2017, 5:CD009865 (incorporated herein by reference in its entirety). [0325] Rayar A M et al. “Update on COX-2 selective inhibitors: chemical classification, side effects and their use in cancers and neuronal diseases.” Curr. Top. Med. Chem. 2017, 17(26):2935-56 (incorporated herein by reference in its entirety). [0326] Miao X P et al. “Role of selective cyclooxygenase-2 inhibitors in exacerbation of inflammatory bowel disease: a systematic review and meta-analysis.” Curr. Ther. Res. 2008, 69(3): 181-91 (incorporated herein by reference in its entirety). [0327] Prabhakaran J et al. “Synthesis of [11C]celecoxib: A potential PET probe for imaging COX-2 expression.” J. Label. Comp. Radiopharm. 2005, 48:887-95 (incorporated herein by reference in its entirety). [0328] Prabhakaran J et al. “Synthesis and in vivo evaluation of [18F]-4-[5-(4-methylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a PET imaging probe for COX-2 expression.” Bioorg. Med. Chem. Lett. 2007, 15:1802-7 (incorporated herein by reference in its entirety). [0329] Toyokuni T et al. “Synthesis of 4-(5-[18F]fluoromethyl-3phenylisoxazol-4-yl)benzenesulfonamide, a new [18F]fluorinated analogue of valdecoxib, as a potential radiotracer for imaging cyclooxygenase-2 with positron emission tomography.” Bioorg. Med. Chem. Lett. 2005, 15:4699-702 (incorporated herein by reference in its entirety). [0330] Prabhakaran J et al. “Radiosynthesis and in vivo evaluation of [11C]MOV as a PET imaging agent for COX-2.” Bioorg. Med. Chem. Lett. 2018, 28(14):2432-5 (incorporated herein by reference in its entirety). [0331] Kaur J et al. “Design, synthesis, and evaluation of an 18F-labeled radiotracer based on celecoxib-NBD for positron emission tomography (PET) imaging of cyclooxygenase-2 (COX-2).” Chem. Med. Chem. 2015, 10:1635-40 (incorporated herein by reference in its entirety). [0332] Wuest F et al. “Synthesis and evaluation in vitro and in vivo of a 11C-labeled cyclooxygenase-2 (COX-2) inhibitor.” Bioorg. Med. Chem. 2008, 16:7662-70 (incorporated herein by reference in its entirety). [0333] De Vries E F J et al. “Synthesis and in vivo evaluation of 18F-desbromo-DuP-697 as a PET tracer for cyclooxygenase-2 expression.” J. Nucl. Med. 2003, 44:1700-6 (incorporated herein by reference in its entirety). [0334] De Vries E F J et al. “Evaluation of [11C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation.” Nucl. Med. Biol. 2008, 35:35-42 (incorporated herein by reference in its entirety). [0335] Tanaka M et al. “Radiosynthesis and evaluation of 11C-labeled diaryl-substituted imidazole and indole derivatives for mapping cyclooxygenase-2.” Biol. Pharm. Bull. 2006, 29:2087-209 (incorporated herein by reference in its entirety). [0336] Pacelli A et al. “Imaging COX-2 expression in cancer using PET/SPECT radioligands: current status and future directions.” J Labelled. Comp. Radiopharm. 2014, 57(4): 317-22 (incorporated herein by reference in its entirety). [0337] Tietz O et al. “Radiotracers for molecular imaging of cyclooxygenase-2 (COX-2) enzyme.” Curr. Med. Chem. 2013, 20(35):4350-69 (incorporated herein by reference in its entirety). [0338] Kumar J S D et al. “In vivo evaluation of [11C]TMI, a COX-2 selective PET tracer, in baboons.” Bioorg. Med. Chem. Lett. 2018, 28(23-24):3592-5 (incorporated herein by reference in its entirety). [0339] Tietz O et al. “PET imaging of cyclooxygenase-2 (COX-2) in a pre-clinical colorectal cancer model.” Eur. J. Nuc. Med. Mol. Imag. Res. 2016, 6(1):37 (incorporated herein by reference in its entirety). [0340] Tietz O et al. “Impact of structural alterations on the radiopharmacological profile of 18F-labeled pyrimidines as cyclooxygenase-2 (COX-2) imaging agents.” Nucl. Med. Biol. 2018, 62-63:9-17 (incorporated herein by reference in its entirety). [0341] Litchfield M et al. “Radiosynthesis and biological evaluation of [18F]triacoxib: a new radiotracer for PET imaging of COX-2.” Mol. Pharm. 2020, 17(1):251-61 (incorporated herein by reference in its entirety). [0342] Kim M-J et al. “Evaluation of two potent and selective PET radioligands to image COX-1 and COX-2 in rhesus monkeys.” J. Nucl. Med. 2018, 59(12): 1907-12 (incorporated herein by reference in its entirety). [0343] Gallagher E et al. “Novel PET radioligands show That COX-2, but not COX-1, is induced by neuroinflammation in rhesus macaque.” Biological Psychiatry Annual Meeting, 2018, 83(9):S160 (incorporated herein by reference in its entirety). [0344] Prabhakaran J et al. “Radiosynthesis and evaluation of [18F]FMTP: a potential COX-2 PET ligand.” J. Nucl. Med. 2019, 60:1106 (incorporated herein by reference in its entirety). [0345] Cortes-Salva M Y et al. “2-(4-Methylsulfonylphenyl)pyrimidines as prospective radioligands for imaging cyclooxygenase-2 with PET-synthesis, triage, and radiolabeling.” Molecules 2018, 23(11):2850 (incorporated herein by reference in its entirety). [0346] Orjales A et al. “Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors.” Bioorg. Med. Chem. 2008, 16(5):2183-99 (incorporated herein by reference in its entirety). [0347] Catorce M N et al. “LPS-induced murine neuroinflammation model: main features and suitability for pre-clinical assessment of nutraceuticals.” Curr. Neuropharmacol. 2016, 14(2): 155-64 (incorporated herein by reference in its entirety). [0348] Font-Nieves M et al. “Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes.” J. Biol. Chem. 2012, 287(9):6454-68 (incorporated herein by reference in its entirety). [0349] Yao R et al. “Performance characteristics of the 3-D OSEM algorithm in the reconstruction of small animal PET images. Ordered-subsets expectation-maximization.” IEEE transactions on medical imaging. 2000, 19, 798-804 (incorporated herein by reference in its entirety). [0350] Yang Z et al. “Dynamic FDG-PET imaging to differentiate malignancies from inflammation in subcutaneous and in situ mouse model for non-small cell lung carcinoma (NSCLC).” PLoS One 2015, 10(9):e0139089 (incorporated herein by reference in its entirety).