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|Title:||Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition|
|Abstract:||This invention relates to novel thioflavin derivatives, methods of using the derivatives in, for example, in vivo imaging of patients having neuritic plaques, pharmaceutical compositions comprising the thioflavin derivatives and method of synthesizing the compounds. The compounds find particular use in the diagnosis and treatment of patients having diseases where accumulation of neuritic plaques are prevalent. The disease states or maladies include but are not limited to Alzheimer's disease, familial Alzheimer's disease, Down's Syndrome and homozygotes for the apolipoprotein E4 allele.|
|Inventor(s):||Klunk; William E. (Pittsburgh, PA), Mathis, Jr.; Chester A. (Pittsburgh, PA), Wang; Yanming (Imperial, PA)|
|Assignee:||University of Pittsburgh--of the Commonwealth System of Higher Education (Pittsburgh, PA)|
|Filing Date:||Dec 17, 2010|
|Claims:||1. An amyloid binding compound having a structure selected from the group consisting of: ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## wherein at least one of the atoms of the structure is replaced with .sup.11C. |
2. An amyloid binding compound according to claim 1 having the following structure ##STR00033## wherein at least one of the atoms of the formula is replaced with .sup.11C.
3. A pharmaceutical composition comprising a compound according to claim 1 or 2 and a pharmaceutically acceptable carrier.
4. A method for detecting amyloid deposits in a subject, comprising the steps of: (a) administering a detectable quantity of a pharmaceutical composition comprising a compound according to claim 1 or 2, and (b) detecting the binding of the compound to amyloid deposit in the subject.
5. The method according to claim 4, wherein the amyloid deposit is located in the brain of a subject.
6. The method according to claim 4, wherein the subject is suspected of having a disease or syndrome selected from the group consisting of Alzheimer's Disease, familial Alzheimer's Disease, Down's Syndrome and homozygotes for the apolipoprotein E4 allele.
7. The method according to claim 4, wherein the detecting is achieved by positron emission tomography.
8. The method according to claim 4, wherein the pharmaceutical composition is administered by intravenous injection.
9. The method according to claim 4, wherein the ratio of (i) binding of the compound to a brain area other than the cerebellum to (ii) binding of the compound to the cerebellum in the subject is compared to the ratio in a normal subject.
10. A method of detecting amyloid deposits in biopsy or post-mortem human or animal tissue comprising the steps of (a) incubating formalin-fixed or fresh-frozen tissue with a solution of an amyloid binding compound according to claim 1 or 2 to form labeled deposits and then (b) detecting the labeled deposits.
11. The method according to claim 10, wherein the solution is composed of 25-100% ethanol, with the remainder of the solution being water, wherein the solution is saturated with the compound.
12. The method according to claim 10, wherein the solution is composed of an aqueous buffer containing 0-50% ethanol, and wherein the solution contains 0.0001 to 100 .mu.M of the compound.
13. The method according to claim 10, wherein the detecting is effected by microscopic techniques selected from the group consisting of bright-field, fluorescence, laser-confocal, and cross-polarization microscopy.
14. A method of quantifying the amount of amyloid in biopsy or post-mortem tissue comprising the steps of (a) incubating a compound according to claim 1 or 2 with a homogenate of biopsy or post-mortem tissue, (b) separating tissue-bound from tissue-unbound compound, (c) quantifying the tissue-bound compound, and (d) converting the units of tissue-bound compound to units of micrograms of amyloid per 100 mg of tissue by comparison with a standard.
15. A method of distinguishing an Alzheimer's disease brain from a normal brain comprising the steps of: (a) obtaining tissue from (i) the cerebellum and (ii) another area of the same brain other than the cerebellum from normal subjects and from subjects suspected of having Alzheimer's disease; (b) incubating the tissues with a compound according to claim 1 or 2, whereby amyloid in the tissue binds with the compound; (c) quantifying the amount of amyloid bound to the compound; (d) calculating the ratio of the amount of amyloid in the area of the brain other than the cerebellum to the amount of amyloid in the cerebellum; (e) comparing the ratio for amount of amyloid in the tissue from normal subjects with the ratio for amount of amyloid in tissue from subjects suspected of having Alzheimer's disease; and (f) determining the presence of Alzheimer's disease if the ratio from the brain of a subject suspected of having Alzheimer's disease is above 90% of the ratios obtained from the brains of normal subjects.
16. A method of selectively binding a compound according to claim 1 or 2 to amyloid plaques but not to neurofibrillary tangles in in vivo brain tissue which contains both, comprising administering an effective amount of the compound so that blood concentration of the administered compound remains below 10 nM in vivo.
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