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WO1998047969B1 - Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition - Google Patents

Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition

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Publication number
WO1998047969B1
WO1998047969B1 PCT/US1998/007889 US9807889W WO9847969B1 WO 1998047969 B1 WO1998047969 B1 WO 1998047969B1 US 9807889 W US9807889 W US 9807889W WO 9847969 B1 WO9847969 B1 WO 9847969B1
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WO
WIPO (PCT)
Prior art keywords
independently
amyloid
following structure
same
lower alkyl
Prior art date
Application number
PCT/US1998/007889
Other languages
French (fr)
Other versions
WO1998047969A1 (en
Filing date
Publication date
Priority claimed from US08/837,494 external-priority patent/US6168776B1/en
Priority to NZ500714A priority Critical patent/NZ500714A/en
Priority to EEP199900503A priority patent/EE9900503A/en
Priority to SK1440-99A priority patent/SK144099A3/en
Priority to KR1019997009642A priority patent/KR20010006552A/en
Priority to BR9809580-3A priority patent/BR9809580A/en
Priority to CA002286607A priority patent/CA2286607A1/en
Priority to AU71369/98A priority patent/AU7136998A/en
Application filed filed Critical
Priority to JP54622398A priority patent/JP2002500634A/en
Priority to IL13242698A priority patent/IL132426A0/en
Priority to HU0003804A priority patent/HUP0003804A3/en
Priority to EP98918448A priority patent/EP0977815A1/en
Priority to PL98336321A priority patent/PL336321A1/en
Publication of WO1998047969A1 publication Critical patent/WO1998047969A1/en
Publication of WO1998047969B1 publication Critical patent/WO1998047969B1/en
Priority to MXPA/A/1999/009557A priority patent/MXPA99009557A/en
Priority to NO995088A priority patent/NO995088L/en

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Abstract

Amyloid binding compounds which are non-azo derivatives of Chrysamine G, pharmaceutical compositions containing, and methods using such compounds to identify Alzheimer's brain in vivo and to diagnose other pathological conditions characterized by amyloidosis, such as Down's Syndrome are described. Pharmaceutical compositions containing non-azo derivatives of Chrysamine G and methods using such compositions to prevent cell degeneration and amyloid-induced toxicity in amyloidosis associated conditions are also described. Methods using non-azo Chrysamine G derivatives to stain or detect amyloid deposits in biopsy or post-mortem tissue are also described. Methods using non-azo Chrysamine G derivatives to quantify amyloid deposits in homogenates of biopsy and post-mortem tissue are also described.

Claims

-107-AMENDED CLAIMS[received by the International Bureau on 25 November 1998 (25.11.98); original claims 1, 14 and 21 amended; remaining claims unchanged (23 pages)]
1. An amyloid binding compound of Formula 1 or a water soluble, non-toxic salt thereof:
Figure imgf000003_0001
Figure imgf000003_0002
wherein: z z - is either , D , CR'=CR\ CR^-CR',, C≡C-C=C, CR'=CR'-CR'=CR',
OC-CR' =CR', or CRVCR'2-CR'2-CR'2 (where each R' independently represents H or a lower al yl group);
X is C(R")2
(wherein each R" independently is H, F, Cl, Br, I, a lower alkyl group, (CIIj^OR' wherein n = l, 2, or 3, CF3, CH2-CII2F, 0-CH2-CH2F, CH2-CH2-CH2F, O-CH2-CH2-CH2F,
CN, (C=0)-R\ N(R')2( N02, (C=0)N(R')2, 0(C0)R', OR', SR\ COOR', R^,
CR' -CR'-R^, CRj'-CRj'-Rp,,, (wherein Rph represents an unsubsiituted or substituted plienyl group with the phenyl substituents being chosen from aαy of the non-phenyl substituents defined from R", a tri-alkyl tin, a tetrazole or oxadiazole of the -108-
form:
Figure imgf000004_0001
wherein R' is H or a lower alkyl group) or X is CR'=CR', N^N, C=0, O, NR* (where R' represents H or a lower alkyl group), S, or S02; each R, and R2 independently is H, F, Cl, Br, I, a lower alkyl group, CHΛOR' wherein n-1, 2, or 3, CF3, CH2-CH2F, O-CH2-CH2F, CH2-CH2-CH2F, 0-CH2-CH2-CH2F, CN, (C=0)-R\ N(R')2, N02, (C=0)N(R')2, 0(CO)R\ OR', SR', COOR', a tri-alkyl tin, R,,,., CR^CR'-Rph, CR,,-CR2'-Rph, (wherein p,, represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from R, and ^ a tri-alkyl tin, a tetrazole or oxadiazolc of the form:
Figure imgf000004_0002
(wherein R' is H or a lower alkyl group), or a triazene of the form:
(wherein R8 and R9 are lower alkyl groups)
Figure imgf000004_0003
or
Figure imgf000004_0004
each Q is indepdently selected from one or the following structures: IA, IB, IC, ID, IE, IF, and IG, wherein -109-
IA has the following structure:
Figure imgf000005_0001
wherein: each of R3, R4, Rs, R^, or R7 independently is defined the same as R, above; IB has the following structure: (IB)
Figure imgf000005_0002
wherein: each of R10, Rn, R12, R13, R1 , Rι„ or R,6 independently is defined the same as Rj above;
IC has die following structure;
Figure imgf000005_0003
wherein: each of R17, R,,,, R19, R^, or R^ independently is defined the same as R, above; -110-
ID has the following structure:
Figure imgf000006_0001
wherein each of RΏ, RJJ, or R^ independently is defined the same as Rt above
Figure imgf000006_0002
represents a heterocyclic ring of one of the six following formulas:
Figure imgf000006_0003
Figure imgf000006_0004
IE has the following structure:
Figure imgf000006_0005
-111-
whercin: each of ^, RM, or R27 independently is defined the same as R, above
\ /
represents a heterocyclic ring of one of the six following formulas:
Figure imgf000007_0001
Figure imgf000007_0002
IF has the following structure:
Figure imgf000007_0003
wherein: z z exactly one of Rjg, ^, R^, R3h or R32 is the v. -112-
link defined for Formula I above and each other -j, R2 , R30, R31, or R32 independently is defined the same as R, above; IG has the following structure:
Figure imgf000008_0001
Figure imgf000008_0002
wherein:
exactly one of R33, R34, R35, R3ft, R37, ^ or R39 is the '- y link defined for Formula I above and each other R33, R34, R35, R3n, R37, R38 or R3„ independently is defined the same as R, above, y 7, with the proviso that when - / is CsC or CR' =CR' then the compounds of Formula I are other than
Figure imgf000008_0003
-113-
2. The compound of claim 1, wherein at least one of the substituents R]τR7 and R10-Rj» is selected from the group consisting of 131I, 1Z3I, "Br, 75Br, lβF, CHz-CHz-^F, 0- CH2-CH2-lβF,
Figure imgf000009_0001
0-CH2-CH2-CH,-lβF, 19F, "SI, and a carbon-containing substituent as specified in Formula I wherein at least one carbon is "C or "C.
3. The compound of claim 1, wherein said compound binds to Aβ with a dissociation constant (1^) between 0.0001 and 10.0 μM when measured by binding to synthetic Aβ peptide or Alzheimer's Disease brain tissue.
4. A method for synthesizing a compound of claim
1, wherein at least one of the substituents Rx-R7 and R10~ R39 is selected from the group consisting of mI, 12SI, USI, 7*Br, 75Br, "F and "F, comprising the step of reacting a ' compound of claim 1, wherein at least one of the substituents 1-R7 and jo-Ras is a tri-alkyl tin or a triazene, with a halogenating agent containing 131I, ia5I, "3I, 7*Br, 75Br, "F or »F.
5. A pharmaceutical composition for in vivo imaging of amyloid deposits, comprising (a) a compound of claim
2, and (b) a pharmaceutically acceptable carrier.
6. An in vivo method for detecting amyloid deposits in a subject, comprising the steps of:
(a) administering a detectable quantity of the pharmaceutical composition of claim 5, and
(b) detecting the binding of said compound to amyloid deposit in said subject.
7. The method of claim 6, wherein said amyloid deposit is located in the brain of a subject. -114-
8. The method of claim 6, wherein said 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.
9. The method of claim 6, wherein said detecting is selected from the group consisting of gamma imaging, magnetic resonance imaging and magnetic resonance spectroscopy.
10. The method of claim 9, wherein said gamma imaging is either PET or SPECT.
11. The method of claim 7, wherein said pharmaceutical composition is administered by intravenous injection.
12. The method of claim 7, wherein the ratio of (i) binding of said compound to a brain area other than the cerebellum to (ii) binding of said compound to the cerebellum, in said subject, is compared to said ratio in normal subjects.
13. A method of inhibiting cell degeneration and toxicity associated with fibril formation in an amyloidosis-associated condition, said method comprising the step of administering to a subject having or suspected of having such condition, a pharmaceutically effective amount of Chrysamine G or a derivative thereof.
14. The method of claim 13, wherein said derivative of Chrysamine G is an amyloid binding compound of Formula I or a water soluble, non-toxic salt thereof:
Figure imgf000011_0001
Figure imgf000011_0002
wherein: z z — ■' is either , CsC, CR^CR', CR2-CR'2, CsC-CsC, CR'=CR'-CR'=CR\
CsC-CR'=CR\ or CR'2-CRyCRyCR'2 (where each R' independendy represents H or a lower alkyl group);
X is C(R")2
(wherein each R" independently is H, F, Cl, Br, I, a lower alkyl group, (CH2)I1OR' wherein n=l, 2, or 3, CF3, CH2-CH2F, 0-CH2-CH2F, CH2-CH2-CH2F, 0-CH2-CH2-CH2F,
CN, (C=0)-R\ N(R')2, N02, (C=0)N(R 0(CO)R', OR', SR', COOR', R^,
CR"=CR'-Rph, CR2'-CR2'-Rph, (wherein R^ represents an unsubsiituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from R", a tri-alkyl tin, a tetrazole or oxadiazole of the form: -116-
Figure imgf000012_0001
wherein R' is H or a lower alkyl group) or X is CR'=CR\ N=N, C=0, O, NR' (where R' represents H or a lower alkyl group), S, or SΩ2; each R, and R2 independently is H, F, Cl, Br, I, a lower alkyl group, (CH^OR' wherein n= l. 2, or 3, CF3, CH2-CHZF,
Figure imgf000012_0002
CH2-CH2-CH2F, 0-CH2-CH2-CH2F, CN, (C=0)-R\ N(R')2, N02, (C=0)N(R')2, 0(CO)R', OR', SR', COOR', a tri-alkyl tin, R^, CR' = CR'-Rph, CR2"-CR2 ,-Rph, (wherein Rph represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from Rt and Rj, a tri-alkyl tin, a tetrazole or oxadiazole of the form:
Figure imgf000012_0003
(wherein R' is H or a lower alkyl group), or a triazene of the form:
(wherein Rg and R9 are lower alkyl groups)
Figure imgf000012_0004
or
Figure imgf000012_0005
each Q is independendy selected from one or the following structures: IA, IB, IC, TD, IE, IF, and IG. wherein
IA has the following structure: -117-
Figure imgf000013_0001
wherein: each of R3, 4, R5, R*, or R7 independently is defined the same as R, above; IB has the following structure: (IB)
Figure imgf000013_0002
wherein: each of Rl0, Rn, Rn, R]3, RM, R)5, or R16 independently is defined the same as Rj above; IC has the following structure:
Figure imgf000013_0003
wherein: each of Rι7, R^, Rm, R20, orv R2ι independently is defined the same as R, above;
ID has the following structure: -118-
Figure imgf000014_0001
wherein each of R22, RB, or R24 independently is defined the same as R, above
\ / and
represents a heterocyclic ring of one of the six following formulas:
Figure imgf000014_0002
Figure imgf000014_0003
IE has the following structure:
Figure imgf000014_0004
-119-
wherein: each of Rjs, R^, or R^ independently is defined the same as R, above
\ / and
represents a heterocyclic ring of one of the six following formulas;
Figure imgf000015_0001
Figure imgf000015_0002
IF has the following structure:
Figure imgf000015_0003
wherein: z exactly one of R^, R29, R30, R3I > or R32 is the — -120-
link defined for Formula I above and each other R^, R^, R^, R31, or R32 independently is defined the same as R, above; IG has the following structure:
Figure imgf000016_0001
Figure imgf000016_0002
wherein:
exactly one of R33, R34, R35, R^, R37> R3g or R39 is the N--- link defined for Formula I above and each other R33, R34, RM, R3β, R37, R3B or R39 independently is defined the same as Rj above,
7, 7. with the proviso that when -y is G≡C or CR'=CR' then the compounds of Formula I are other than
Figure imgf000016_0003
-121-
15. The method of claim 13, wherein said amyloidosis-associated condition is selected from the group consisting of Alzheimer's Disease, Down's Syndrome, Type 2 diabetes mellitus, hereditary cerebral hemorrhage amyloidosis (Dutch) , amyloid A (reactive) , secondary amyloidosis, familial mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome) , amyloid lambda L-chain or amyloid kappa L-chain (idiopathic, myeloma or macroglobulinemia-associated) A beta 2M (chronic he odialysiε) , ATTR (familial amyloid polyneuropathy
(Portuguese, Japanese, Swedish) , familial amyloid cardiomyopathy (Danish) , isolated cardiac amyloid, (systemic senile amyloidosises) , AIAPP or a ylin insulinoma, atrial naturetic factor (isolated atrial amyloid) , procalcitonin (medullary carcinoma of the thyroid), gelsolin (familial amyloidosis (Finnish)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic)), AApo-A-I (familial amyloidotic polyneuropathy - Iowa) , AΛpo-A-II (accelerated senescence in mice) , fibrinogeπ-associated amyloid; and Asor or Pr P-27 (scrapie, Creutzfeld Jacob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis) or in cases of persons who are homozygous for the apolipoprotein E4 allele, and the condition associated with homozygosity for the apolipoprotein E4 allele.
16. A pharmaceutical composition for the prevention of cell degeneration and toxicity associated with fibril formation in amyloidosis-associated conditions comprising a Chrysamine G derivative of claim 1 and a
pharmaceutically acceptable carrier. -122-
17. A method of detecting amyloid deposits in biopsy or post-mortem human or animal tissue comprising the steps of:
(a) incubating formalin-fixed tissue with a solution of a compound of claim 1 to form a labelled deposit and then,
(b) detecting the labelled deposits.
18. The method of claim 17 wherein said solution is composed of 25-100% ethanol (the remainder being water) saturated with a compound of claim 1.
19. The method of claim 17 wherein said detecting is effected by microscopic techniques selected from the group consisting of bright-field, fluorescence, laser- confocal, and cross-polarization microscopy.
20. A method of quantifying the amount of amyloid in biopsy or post-mortem tissue comprising the steps of: a) incubating a radiolabeled derivative of Chrysamine G with a homogenate of biopsy or postmortem tissue, b) separating the tissue-bound from the tissue- unbound radiolabeled Chrysamine G derivative, c) quantifying the tissue-bound radiolabeled Chrysamine G derivative, and d) converting the units of tissue-bound radiolabeled
Chrysamine G derivative to units of micrograms of amyloid per 100 g of tissue by comparison with a standard. -123-
21. The method of claim 20, wherein said radiolabeled derivative of Chrysamine G is an amyloid binding compound of Formula I or a water soluble, non-toxic salt thereof:
Figure imgf000019_0001
Figure imgf000019_0002
wherein:
Figure imgf000019_0003
C=C-CR' =CR', or CR'2-CR'2-CR'2-CR'2 (where each R* independently represents H or a lower alkyl group);
X is C(R")2
(wherein each R" independently is H, F, Cl, Br, I, a lower alkyl group, (CHj)nOR' wherein n=l, 2, or 3, CF3, CH2-CH2F, 0-CH2-CH2F, CH2-CH2-CH2F, 0-CH2-CH2-CH2F,
CN, (C-0)-R\ N(R N02, (C=0)N(R,)ι, 0(CO)R', OR'. SR', COOR', R.h,
CR' = CR'-R-h, CR2'-CR2'-Rph, (wherein Rp,, represents an unsubsti ted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from R", a tri-alkyl tin, a tetrazole or uxadiazole of die form: -124-
Figure imgf000020_0001
wherein R' is H or a lower alkyl group) or X is CR'=CR\ N=N, C=0, O, NR' (where R' represents H or a lower alkyl group), S, or S02; each R, and Rz independently is H, F, Cl, Br, I, a lower alkyl group, (CH^OR' wherein n=l, 2, or 3, CF3, CH2-CH2F, 0-CH2-CH2F, CH2-CH2-CH2F, O-CHj-CHj-CHjF, CN, (C=0)-R\ N(R')2, N02, (C=0)N(R')2, O(CO)R', OR', SR', COOR'. a tri-alkyl tin, CR' CRz'-CRj'-Rph, (wherein Rp,. represents an unsubsiituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined from R, and ,, a tri-alkyl tin, a tetrazole or oxadiazule of the form:
Figure imgf000020_0002
(wherein R' is FI or a lower alkyl group), or a triazene of the form:
(wherein R8 and R,} are lo er alkyl groups)
Figure imgf000020_0003
or
Figure imgf000020_0004
each is indepdently selected from one or the following structures: IA, IB, IC, ED, IE, IF, and IG, wherein
IA has the following structure: -125-
Figure imgf000021_0001
wherein: each of R3, R4, Rj, R6, or R7 independently is defined the same as R, above; IB has the following structure:
OB)
Figure imgf000021_0002
wherein: each of R10, R„, R12, R13, Rl4, R,5, or Rl6 independently is defined the same as R, above; IC has the following structure:
Figure imgf000021_0003
wherein: each of R]7, R18, R19, R^,, or Rjt independently is defined the same as R, above;
ID has the following structure: -126-
Figure imgf000022_0001
wherein each of R^, ^, or R^ independently is defined the same as R, above
Figure imgf000022_0002
represents a heterocycUc ring of one of the six following formulas:
Figure imgf000022_0003
Figure imgf000022_0004
IE has the following structure;
Figure imgf000022_0005
wherein: -127-
each of R^j, R26, or R27 independently is defined the same as R, above
\ / and
represents a heterocyclic ring of one of the six following formulas:
Figure imgf000023_0001
Figure imgf000023_0002
IF has the following structure:
Figure imgf000023_0003
wherein:
exactly one of R^, RM, ^,, R , or R3Z is the - link defined for Formula I above and each other R2R, ^,, R30, R,,, or R32 independently is defined the same as R, above; -128-
IG has the following structure:
Figure imgf000024_0001
Figure imgf000024_0002
wherein: z z exactly one of RMf R,4, R35, R36, R37, R38 or R39 is the "- J γ^ defined for Formula I above and each other R33, R-4. R35, ,b> R37, R38 or R3D independently is defined the same as R, above, 7. with the proviso that when '-- ' is C-C or CR' =CR' then the compounds of Formula 1 are other than
Figure imgf000024_0003
-129-
22. The method of claim 21 wherein at least one of the substituents Rι~R7 and R10-R39 is labeled with a radiolabel selected from the group consisting of lϊ5I, 3H,. and a carbon-containing substituent as specified in Formula I, wherein at least one carbon is l*C.
23. 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 said tissues with a radiolabeled Chrysamine G derivative so that amyloid in said tissue binds with said radiolabeled Chrysamine G derivative; c) quantifying the amount of amyloid bound to said radiolabeled Chrysami e G derivative, according to the method of claim 20; 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 said ratio for amount of amyloid in said tissue from normal subjects with 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 said 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.
PCT/US1998/007889 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition WO1998047969A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
PL98336321A PL336321A1 (en) 1997-04-18 1998-04-20 Alkyl, alkylene and alkinyl derivatives of chrysamine g for postmortem diagnosing the alzeheimer disease and in vivo imaging presence of amyloide as well as preventing accumulation thereof
JP54622398A JP2002500634A (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynylchrysamine G derivatives for diagnosing Alzheimer's disease in life, imaging amyloid deposits in vivo, and preventing amyloid deposition
SK1440-99A SK144099A3 (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosis of alzheimer's disease and i(in vivo) imaging and prevention of amyloid deposition
KR1019997009642A KR20010006552A (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
BR9809580-3A BR9809580A (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl g chrysamine derivatives for diagnosis before death from alzheimer's disease and in vivo diagnosis through imaging and prevention of amyloid deposition
CA002286607A CA2286607A1 (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
AU71369/98A AU7136998A (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl Chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
NZ500714A NZ500714A (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl Chrysamine G derivatives useful fro the antemortem diagnosis of Alzheimer's Disease and in vivo imaging and prevention of amyloid deposition
HU0003804A HUP0003804A3 (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
EEP199900503A EE9900503A (en) 1997-04-18 1998-04-20 Alkyl, alkenyl and alkynyl derivatives of Chrysamine G for ante mortem diagnosis of Alzheimer's disease, prevention and imaging of amyloid deposition
IL13242698A IL132426A0 (en) 1997-04-18 1998-04-20 An amyloid binding compound and pharmaceutical compositions containing the same
EP98918448A EP0977815A1 (en) 1997-04-18 1998-04-20 ALKYL, ALKENYL AND ALKYNYL CHRYSAMINE G DERIVATIVES FOR THE ANTEMORTEM DIAGNOSIS OF ALZHEIMER'S DISEASE AND $i(IN VIVO) IMAGING AND PREVENTION OF AMYLOID DEPOSITION
NO995088A NO995088L (en) 1997-04-18 1999-10-18 Alkyl, alkenyl and alkynyl chrysamine G derivatives for pre-diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
MXPA/A/1999/009557A MXPA99009557A (en) 1997-04-18 1999-10-18 Alkyl, alkenyl and alkynyl chrysamine g derivatives for the antemortem diagnosis of alzheimer's disease and (in vivo) imaging and prevention

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US08/837,494 US6168776B1 (en) 1994-07-19 1997-04-18 Alkyl, alkenyl and alkynyl Chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition

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