Imaging agents for detecting neurological dysfunction
Disclosed here in are compounds and methods of diagnosing Alzheimer's Disease or a predisposition thereto in a mammal, the method comprising administering to the mammal a diagnostically effective amount of a radiolabeled compound, wherein the compound is selected from the group consisting of radiolabeled flavones, coumarins, carbazoles, quinolinones, chromenones, imidazoles and triazoles derivatives, allowing the compound to distribute into the brain tissue, and imaging the brain tissue, wherein an increase in binding of the compound to the brain tissue compared to a normal control level of binding indicates that the mammal is suffering from or is at risk of developing Alzheimer's Disease.
1. A compound or a pharmaceutically acceptable salt thereof represented by the formula Ic:
wherein
L is N or CR 5 where R 5 is H;
M is N or CR 6 where R 6 is H;
R 3 is alkylamino, arylamino, cycloalkylamino, heteroarylamino, halo-C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, H(OCH 2 CH 2 ) 1-6 O, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, or heteroaryloxy;
wherein at least one hydrogen of R 3 is replaced with, or a radionuclide selected from the group consisting of 18 F, 77 Br, 123 I, 125 I, and 131 I.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein M is N and L is CR 5 .
3. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein R 3 is amino, halo-C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 cycloalkylC 1-5 alkyl, C 6-14 aryl, C 6-10 arylC 1-4 alkyl, heteroaryl, H(OCH 2 CH 2 ) 1-6 O, C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O, halo-C 1-5 alkoxy, halo-C 1-3 alkyl(OCH 2 CH 2 ) 1-6 O, C 3-6 cycloalkoxy, C 3-12 cycloalkylC 1-5 alkoxy, heteroarylC 2-5 alkoxy, C 6-14 aryloxy, C 6-10 arylC 1-4 alkoxy, or heteroaryloxy.
4. The compound or a pharmaceutically acceptable salt thereof according to claim 3 , wherein:
R 3 is a pyridine having at least one hydrogen replaced by halo or a radionuclide selected from the group consisting of 18 F, 123 I, 125 I, and 131 .
5. The compound or a pharmaceutically acceptable salt thereof according to claim 4 , wherein the pyridine has at least one hydrogen replaced by halo or a radionuclide selected from the group consisting of 18 F, 77 Br, 123 I, 125 I, and 131 I.
6. A pharmaceutical composition for in vivo imaging of amyloid deposits and tau tangles, comprising (a) the compound or a pharmaceutically acceptable salt thereof according to claim 1 and (b) a pharmaceutically acceptable carrier.
7. A method of diagnosing Alzheimer's Disease or a predisposition thereto in a mammal, the method comprising:
a) administering to the mammal a diagnostically effective amount of the compound or a pharmaceutically acceptable salt according to claim 1 ;
b) allowing the compound to distribute into the brain tissue; and
c) imaging the brain tissue, wherein an increase in binding of the compound to the brain tissue compared to a normal control level of binding indicates that the mammal is suffering from or is at risk of developing Alzheimer's Disease.
8. The method of claim 7 , wherein the compound or a pharmaceutically acceptable salt thereof binds to tau tangles.
9. The method of claim 7 , which further comprises imaging by employing a fluorescence imaging technique or a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT), the fluorescence imaging technique and/or nuclear imaging technique for monitoring or visualizing a distribution of the radiolabeled or tagged compound within the brain or within a portion thereof.