Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition

Patent metadata

Field	Value
Publication number	US-10137210-B2
Application number	US-201715726314-A
Country	US
Kind code	B2
Filing date	Oct 5, 2017
Priority date	Aug 24, 2000
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

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.

First claim

What is claimed is:

1. An amyloid binding compound having a structure selected from the group consisting of:

wherein at least one of the atoms of the structure is replaced with 3 H.

2. The compound according to claim 1 , wherein the compound is:

3. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

5. 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 , and
(b) detecting binding of the compound to amyloid deposit in the subject.

6. The method according to claim 5 , wherein the amyloid deposit is located in the brain of the subject.

7. The method according to claim 5 , 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.

8. The method according to claim 5 , wherein the detecting of step (b) is achieved by positron emission tomography.

9. The method according to claim 5 , wherein the pharmaceutical composition is administered by intravenous injection.

10. The method according to claim 5 , 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.

11. 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 obtained from a biopsy or post-mortem human or animal tissue with a solution of an amyloid binding compound according to claim 3 to form labeled deposits; and
(b) detecting the labeled deposits.

12. The method according to claim 11 , wherein the solution is composed of about 25%-about 100% ethanol, with the remainder of the solution being water, wherein the solution is saturated with the compound.

13. The method according to claim 11 , wherein the solution comprises an aqueous buffer comprising 0% about 50% ethanol, and wherein the solution comprises 0.0001 to 100 μM of the compound.

14. The method according to claim 11 , wherein the detecting of step (b) is effected by microscopic techniques selected from the group consisting of bright-field, fluorescence, laser-confocal, and cross-polarization microscopy.

15. 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 with a homogenate of a biopsy or post-mortem tissue,
(b) separating tissue-bound from tissue-unbound compound,
(c) quantifying the tissue-bound compound, and
(d) converting units of tissue-bound compound to units of micrograms of amyloid per 100 mg of tissue by comparison with a standard.

16. 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 of (i) and (ii) with a compound according to claim 1 , 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 of the amount of amyloid in the tissue from normal subjects with the ratio of the 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 about 90% of the ratios obtained from the brains of normal subjects.

17. A method of selectively binding a compound according to claim 1 to amyloid plaques but not to neurofibrillary tangles in in vivo brain tissue which comprises both, wherein the method comprises administering an effective amount of the compound so that blood concentration of the administered compound remains below 10 nM in vivo.

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education
• The Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Klunk William E
• Mathis Jr Chester A
• Wang Yanming

Classifications

• G01N2800/387

  Down syndrome; Trisomy 18; Trisomy 13 · CPC title

• G01N2800/2821

  Alzheimer · CPC title

• G01N2333/4709

  Amyloid plaque core protein · CPC title

• A61K51/0453 Primary

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title