Imaging agents for detecting neurological disorders
Imaging agents of formula (I) and methods for detecting neurological disorders comprising administering ti a patient in need compounds of formula (I) capable of binding to tau proteins and β-amyloid peptides are presented herein. The invention also relates to methods of imaging Aβ and tau aggregates comprising introducing a detectable quantity of pharmaceutical formulation comprising a radiolabeled compound of formula (I) and detecting the labeled compound associated with amyloid deposits and/or tau proteins in a patient. These methods and compositions enable preclinical diagnosis and monitoring progression of AD and other neurological disorders.
1. A compound of Formula (I):
wherein
A is a bond, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 4 )alkene, or (C 2 -C 4 )alkyne;
Z is:
wherein
X 1 and X 13 are each independently C, CH, N, O, or S;
X 2 -X 4 , X 9 -X 12 and X 14 -X 18 are each independently C, CH or N;
R 1 -R 2 are each independently H, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, —(O—CH 2 —CH 2 ) n — (PEG), monoalkylamino, dialkylamino, monoarylamino, diarylamino, NR 10 COOalkyl, NR 10 COOaryl, NR 10 COalkyl, NR 10 CO aryl, COOalkyl, COOaryl, COalkyl, COaryl, aryl, saturated heterocyclyl, wherein the last seventeen groups are unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, alkoxy, R 10 , a radiolabel or alkyl substituted with a radiolabel;
R 5 -R 9 are each independently H, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, —(O—CH 2 —CH 2 ) n —, monoalkylamino, dialkylamino, monoarylamino, diarylamino, NR 10 COOalkyl, NR 10 COOaryl, NR 10 COalkyl, NR 10 CO aryl, COOalkyl, COOaryl, COalkyl, COaryl, aryl, heterocyclyl, wherein the last seventeen groups are unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, alkoxy, R 10 , a radiolabel or alkyl substituted with a radiolabel;
R 10 is H, alkyl, alkene, aryl unsubstituted or substituted with halogen, hydroxyl, cyano, nitro, amino, —OSO 2 alkyl, —OSO 2 aryl, —OSi(alkyl) 3 , —OTHP or a radiolabel;
n is 1, 2, or 3;
m is 1,
wherein at least one of R 1 -R 2 and R 5 -R 9 comprises a radiolabel selected from the group consisting of 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I, 76 Br and 77 Br,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the radiolabel is 18 F.
3. The compound of claim 1 , wherein A is a bond.
4. The compound of claim 1 , wherein at least one of R 1 -R 2 and R 5 -R 9 is —(O—CH 2 —CH 2 ) 2 —.
5. The compound of claim 1 , wherein at least one of X 9 -X 18 is nitrogen.
6. The compound of claim 5 , wherein X 13 is N.
7. The compound of claim 6 , wherein X 1 -X 4 are independently C.
8. The compound of claim 7 , wherein X 14 is N.
9. The compound of claim 8 , wherein X 18 is N.
10. The compound of claim 9 , wherein X 9 -X 12 and X 15 -X 17 are independently C.
11. The compound of claim 10 , wherein R 5 -R 9 are independently H.
12. The compound of claim 1 , wherein R 5 -R 9 are independently H.
13. The compound of claim 11 , wherein R 2 is H.
14. The compound of claim 12 , wherein R 2 is H.
15. The compound of claim 13 , wherein R 1 is PEG.
16. The compound of claim 13 , wherein R 1 is alkyl.
17. A compound of Formula
wherein M is selected from the group consisting of halo or a radionuclide.
18. The compound of claim 17 , wherein M is 18 F.
19. The compound of claim 5 , wherein X 1 -X 4 are independently CH.
20. The compound of claim 6 , wherein R 2 is H.