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Claims for Patent: 7,351,401

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Claims for Patent: 7,351,401

Title:Thioflavin derivatives for use in the antemortem diagnosis of Alzheimers 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 (Pittsburgh, PA)
Application Number:10/859,600
Patent Claims: 1. An amyloid binding compound of the following formula or a water soluble, non-toxic salt thereof: ##STR00057## wherein Z is S, NR', O or CR', wherein when Z is CR', then the correct tautomeric form of the heterocyclic ring containing Z and N is an indole in which R' is H or a lower alkyl group: ##STR00058## Y is NR.sup.1R.sup.2, OR.sup.2, or SR.sup.2; wherein the nitrogen of ##STR00059## is not a quaternary amine; each R.sup.1 and R.sup.2 independently is selected from the group consisting of H, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), (C.dbd.O)--R', R.sub.ph, and (CH.sub.2).sub.nR.sub.ph (wherein n=1, 2, 3, or 4 and R.sub.ph represents an unsubstituted or substituted phenyl group, wherein substituents of R.sub.ph are selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR' (wherein R' is H or a lower alkyl group), a tri-alkyl tin and a chelating group (with or without a chelated metal group) of the form W-L or V-W-L, wherein V is selected from the group consisting of --COO--, --CO--, --CH.sub.2O-- and --CH.sub.2NH--; W is --(CH.sub.2), where n=0,1,2,3,4, or 5; and L is: ##STR00060## wherein M is selected from the group consisting of Tc and Re; and R' is H or a lower alkyl group); each R.sup.3-R.sup.10 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR', R.sub.ph, CR'.dbd.CR'--R.sub.ph, CR.sub.2'--CR.sub.2'-R.sub.ph (wherein R.sub.ph represents an unsubstituted or substituted phenyl group wherein R' is H or a lower alkyl group), a tri-alkyl tin and a chelating group (with or without a chelated metal group) of the form W-L or V-W-L, wherein V is selected from the group consisting of --COO--, --CO--, --CH.sub.2O-- and --CH.sub.2NH--; W is --CH.sub.2).sub.n where n=0,1,2,3,4, or 5; and L is: ##STR00061## wherein M is selected from the group consisting of Tc and Re; or each R.sup.1 and R.sup.2 is a chelating group (with or without a chelated metal group) of the form W-L, wherein W is --CH.sub.2).sub.n where n=2,3,4, or 5; and L is: ##STR00062## wherein M is selected from the group consisting of Tc and Re; or wherein each R.sup.3-R.sup.10 independently is selected from the group consisting of a chelating group (with or without a chelated metal ion) of the form W-L and V-W-L, wherein V is selected from the group consisting of --COO--, and --CO--; W is --CH.sub.2).sub.n where n=0,1,2,3,4, or 5; L is: ##STR00063## and wherein R.sup.15 independently is selected from the following: ##STR00064## or an amyloid binding, chelating compound (with or without a chelated metal group) or a water soluble, non-toxic salt thereof of the form: ##STR00065## wherein R.sup.15 independently is selected from the following: ##STR00066## and R.sup.16 is ##STR00067## wherein Q is independently selected from one of the following structures: ##STR00068## Z is S, NR', O, or C(R').sub.2 in which R' is H or a lower alkyl group; U is N or CR'; Y is NR.sup.1R.sup.2, OR.sup.2, or SR.sup.2; each R.sup.17-R.sup.24 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR', R.sub.ph, CR'.dbd.CR'--R.sub.ph and CR.sub.2'--CR.sub.2'--R.sub.ph (wherein R.sub.ph represents an unsubstituted or substituted phenyl group and wherein R' is H or a lower alkyl group); wherein at least one of the substituents R.sup.1-R.sup.10 is selected from the group consisting of .sup.3H, .sup.131I, .sup.125I, .sup.123I, .sup.76Br, .sup.75Br, .sup.18F, CH.sub.2--CH.sub.2--X*, O--CH.sub.2--CH.sub.2--X*, CH.sub.2--CH.sub.2--CH.sub.2--X*, O--CH.sub.2--CH.sub.2--CH.sub.2--X* (wherein X*=.sup.131I, .sup.123I, .sup.76Br, .sup.75Br or .sup.18F), .sup.19F, .sup.125I, a carbon-containing substituent selected from the group consisting of lower alkyl, (CH.sub.2).sub.nOR', CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', (C.dbd.O)N(R').sub.2, O(CO)R', COOR', CR'.dbd.CR'--R.sub.ph and CR.sub.2'-CR.sub.2'-R.sub.ph wherein at least one carbon is .sup.11C, .sup.13C or .sup.14C and a chelating group (with chelated metal group) of the form W-L* or V-W-L*, wherein V is selected from the group consisting of --COO--, --CO--, --CH.sub.2O-- and --CH.sub.2NH--; W is --(CH.sub.2), where n=0,1,2,3,4, or 5; and L* is: ##STR00069## wherein M* is .sup.99mTc; or L* is: ##STR00070## and wherein R.sup.15 independently is selected from the following: ##STR00071## or a chelating compound (with chelated metal group) of the form: ##STR00072## wherein R.sup.15 independently is selected from the following: ##STR00073## and R.sup.16 is ##STR00074## wherein Q is independently selected from one of the following structures: ##STR00075## Z is S, NR', O, or C(R').sub.2 in which R' is H or a lower alkyl group; U is N or CR'; Y is NR.sup.1R.sup.2, OR.sup.2, or SR.sup.2; wherein each R.sup.17--R.sup.24 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR', R.sub.ph, CR'.dbd.CR'--R.sub.ph and CR.sub.2'--CR.sub.2'--R.sub.ph (wherein R.sub.ph represents an unsubstituted or substituted phenyl group and wherein R' is H or a lower alkyl group).

2. The compound of claim 1, wherein the radiolabel of one of substituents R.sup.3-R.sup.10 is selected from the group consisting of .sup.131I, .sup.123I, .sup.18F, .sup.11C, .sup.75Br and .sup.76Br.

3. The compound of claim 2, wherein the radiolabel of one of substituents R.sup.3-R.sup.10 is selected from the group consisting of .sup.11C and .sup.18F.

4. The compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R.sup.1.dbd.H; and R.sup.2 is selected from the group consisting of (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), (C.dbd.O)--R', R.sub.ph, and (CH.sub.2).sub.nR.sub.ph (wherein n=1, 2, 3, or 4) wherein when R.sup.2 is CH.sub.2R.sub.ph R.sup.8 is not CH.sub.3.

5. The compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R.sup.1.dbd.H, R'.dbd.H, R.sup.2.dbd.CH.sub.3 and R.sup.3-R.sup.10 are H.

6. The compound of claim 1, wherein Z.dbd.S, Y.dbd.O, R'.dbd.H, R.sup.2.dbd.CH.sub.3 and R.sup.3-R.sup.10 are H.

7. The compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R'.dbd.H, R.sup.1-R.sup.4.dbd.H, R.sup.5.dbd.I, and R.sup.6-R.sup.10 are H.

8. The compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R'.dbd.H, R.sup.1-R.sup.4.dbd.H, R.sup.5.dbd.I, R.sup.8OH and R.sup.6-R.sup.7 and R.sup.9-R.sup.10 are H.

9. The compound of claim 1, wherein, Z.dbd.S, Y.dbd.N, R.sup.1.dbd.H, R'.dbd.H, R.sup.2.dbd.CH.sub.2--CH.sub.2--CH.sub.2--F and R.sup.3-R.sup.10 are H.

10. The compound of claim 1, wherein, Z.dbd.S, Y.dbd.O, R'.dbd.H, R.sup.2.dbd.CH.sub.2--CH.sub.2--F and R.sup.3-R.sup.10 are H.

11. The compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R'.dbd.H, R.sup.1-R.sup.7.dbd.H, R.sup.8.dbd.O--CH.sub.2--CH.sub.2--F and R.sup.9-R.sup.10 are H.

12. The compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R'.dbd.H, R.sup.1.dbd.CH.sub.3, R.sup.2-R.sup.7.dbd.H, R.sup.8.dbd.O--CH.sub.2--CH.sub.2--F and R.sup.9-R.sup.10 are H.

13. The compound of claim 4, wherein at least one of the substituents R.sup.3-R.sup.10 is selected from the group consisting of CN, OCH.sub.3, OH and NH.sub.2.

14. The compound of claim 1, wherein R.sup.1.dbd.H, R.sup.2.dbd.CH.sub.3 and R.sup.8 is selected from the group consisting of CN, CH.sub.3, OH, OCH.sub.3 and NH.sub.2.

15. The compound of claim 14, wherein R.sup.3-R.sup.7 and R.sup.9-R.sup.10 are H.

16. The compound of claim 1, having the structure: ##STR00076##

17. The compound of claim 1, having the structure: ##STR00077##

18. The compound of claim 1, having the structure: ##STR00078##

19. The compound of claim 1, having the structure: ##STR00079##

20. The compound of claim 1, having the structure: ##STR00080##

21. The compound of claim 1, having the structure: ##STR00081##

22. A method for synthesizing a compound of claim 1 having at least one of the substituents R.sup.3 -R.sup.10 selected from the group consisting of .sup.131I, .sup.125I, .sup.123I, .sup.76Br, .sup.75Br, .sup.18F, and .sup.19F, comprising the step of labeling a compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R.sup.1.dbd.H and at least one of the substituents R.sup.3-R.sup.10 is a tri-alkyl tin, by reaction of the compound with a .sup.131I, .sup.125I, .sup.123I, .sup.76Br, .sup.75Br, .sup.18F, or .sup.19F containing substance.

23. A pharmaceutical composition for in vivo imaging of amyloid deposits, comprising (a) a compound of claim 1 and (b) a pharmaceutically acceptable carrier.

24. A pharmaceutical composition for in vivo imaging of amyloid deposits, comprising (a) a compound of claim 1, wherein Z.dbd.S, Y.dbd.N, R.sup.1.dbd.H, and (b) a pharmaceutically acceptable carrier.

25. 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 23, and (b) detecting the binding of the compound to amyloid deposit in the subject.

26. The method of claim 25, wherein the amyloid deposit is located in the brain of a subject.

27. The method of claim 25, 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.

28. The method of claim 25, wherein the detecting is selected from the group consisting of gamma imaging, magnetic resonance imaging and magnetic resonance spectroscopy.

29. The method of claim 28, wherein the detecting is done by gamma imaging, and the gamma imaging is either PET or SPECT.

30. The method of claim 25, wherein the pharmaceutical composition is administered by intravenous injection.

31. The method of claim 25, 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 normal subjects.

32. 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 a compound of claim 1 to form a labeled deposit and then, (b) detecting the labeled deposits.

33. The method of claim 32 wherein the solution is composed of 25-100% ethanol, with the remainder of the solution being water, wherein the solution is saturated with an amyloid binding compound of the following formula or a water soluble, non-toxic salt thereof: ##STR00082## wherein Z is S, NR', O or CR' wherein when Z is CR', then the correct tautomeric form of the heterocyclic ring containing Z and N is an indole in which R' is H or a lower alkyl group: ##STR00083## Y is NR.sup.1R.sup.2, OR.sup.2, or SR.sup.2; wherein the nitrogen of ##STR00084## is not a quaternary amine; each R.sup.1 and R.sup.2 independently is selected from the group consisting of H, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), (C.dbd.O)--R', R.sub.ph, and (CH.sub.2).sub.nR.sub.ph (wherein n=1, 2, 3, or 4 and R.sub.ph represents an unsubstituted or substituted phenyl group, wherein substituents of R.sub.ph are selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2----CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR', (wherein R' is H or a lower alkyl group), a tri-alkyl tin and a chelating group (with or without a chelated metal group) of the form W-L or V-W-L, wherein V is selected from the group consisting of --COO--, --CO--, --CH.sub.2O-- and --CH.sub.2NH--; W is --(CH.sub.2).sub.n where n=0,1,2,3,4, or 5; and L is: ##STR00085## wherein M is selected from the group consisting of Tc and Re; and R' is H or a lower alkyl group; each R.sup.3-R.sup.10 are independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH .sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR', R.sub.ph, CR'.dbd.CR'--R.sub.ph, CR.sub.2', --CR.sub.2'--R.sub.ph (wherein R.sub.ph represents an unsubstituted or substituted phenyl group wherein R' is H or a lower alkyl group), a tri-alkyl tin and a chelating group (with or without a chelated metal group) of the form W-L or V-W-L, wherein V is selected from the group consisting of --COO--, --CO--, --CH.sub.2O-- and --CH.sub.2NH--; W is --(CH.sub.2).sub.n where n=0,1,2,3,4, or 5; and L is: ##STR00086## wherein M is selected from the group consisting of Tc and Re; or each R.sup.1 and R.sup.2 is a chelating group (without a chelated metal group) of the form W-L wherein W is --(CH.sub.2).sub.n where N=2,3,4, or 5; and L is: ##STR00087## wherein M is selected from the group consisting of Tc and Re; or wherein each R.sup.3-R.sup.10 independently is selected from the group consisting of a chelating group (with or without a chelated metal ion) of the form W-L and V-W-L, wherein V is selected from the group consisting of --COO--, and --CO--; W is --(CH.sub.2).sub.n where n=0,1,2,3,4, or 5; L is: ##STR00088## and wherein R.sup.15 independently is selected from the following: ##STR00089## or an amyloid binding, chelating compound (with or without a chelated metal group) or a water soluble, non-toxic salt thereof of the form: ##STR00090## wherein R.sup.15 independently is selected from the following: ##STR00091## and R.sup.16 is ##STR00092## wherein Q is independently selected from one of the following structures: ##STR00093## Z is S, NR', O, or C(R').sub.2 in which R' is H or a lower alkyl group; U is N or CR'; Y is NR.sup.1R.sup.2, OR.sup.2, or SR.sup.2; each R.sup.17--R.sup.24 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR', R.sub.ph, CR'.dbd.CR'--R.sub.ph and CR.sub.2'--CR.sub.2'--R.sub.ph (wherein R.sub.ph represents an unsubstituted or substituted phenyl group and wherein R' is H or a lower alkyl group); wherein at least one of the substituents R.sup.1-R.sup.10 is selected from the group consisting of .sup.3H, .sup.131I, .sup.125I, .sup.123I, .sup.76Br, .sup.75Br, .sup.18F, CH.sub.2--CH.sub.2--X*, O--CH.sub.2--CH.sub.2--X*, CH.sub.2--CH.sub.2--CH.sub.2--X*, O--CH.sub.2--CH.sub.2--CH.sub.2--X* (wherein X*=.sup.131I, .sup.123I, .sup.76Br, .sup.75Br or .sup.18F), .sup.19F, .sup.125I, a carbon-containing substituent selected from the group consisting of lower alkyl, (CH.sub.2).sub.nOR', CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', (C.dbd.O)N(R').sub.2, O(CO)R', COOR', CR'.dbd.CR'--R.sub.ph and CR.sub.2'--CR.sub.2'--R.sub.ph wherein at least one carbon is .sup.11C, .sup.13C or .sup.14C and a chelating group (with chelated metal group) of the form W-L* or V-W-L*, wherein V is selected from the group consisting of --COO--, --CO--, --CH.sub.2O-- and --CH.sub.2NH--; W is --CH.sub.2), where n=0,1,2,3,4, or 5; and L* is: ##STR00094## wherein M* is .sup.99mTc; or L* is: ##STR00095## and wherein R.sup.15 independently is selected from the following: ##STR00096## or a chelating compound (with chelated metal group) of the form: ##STR00097## wherein R.sup.15 independently is selected from the following: ##STR00098## and R.sup.16 is ##STR00099## wherein Q is independently selected from one of the following structures: ##STR00100## Z is S, NR', O, or C(R').sub.2 in which R' is H or a lower alkyl group; U is N or CR'; Y is NR.sup.1R.sup.2, OR.sup.2, or SR.sup.2; wherein each R.sup.17-R.sup.24 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH.sub.2).sub.nOR' (wherein n=1, 2, or 3), CF.sub.3, CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2X, CH.sub.2--CH.sub.2--CH.sub.2X, O--CH.sub.2--CH.sub.2--CH.sub.2X (wherein X.dbd.F, Cl, Br or I), CN, (C.dbd.O)--R', N(R').sub.2, NO.sub.2, (C.dbd.O)N(R').sub.2, O(CO)R', OR', SR', COOR', R.sub.ph, CR'.dbd.CR'--R.sub.ph and CR.sub.2'--CR.sub.2'--R.sub.ph (wherein R.sub.ph represents an unsubstituted or substituted phenyl group and wherein R' is H or a lower alkyl group).

34. The method of claim 32 wherein the solution is composed of an aqueous buffer containing 0-50% ethanol, wherein the solution contains 0.0001 to 100 .mu.M of the amyloid binding compound.

35. The method of claim 32 wherein the detecting is effected by microscopic techniques selected from the group consisting of bright-field, fluorescence, laser-confocal, and cross-polarization microscopy.

36. A method of quantifying the amount of amyloid in biopsy or post-mortem tissue comprising the steps of: a) incubating a radiolabeled compound of claim 1 with a homogenate of biopsy or post-mortem tissue, wherein at least one of the substituents R.sup.1-R.sup.10 of the compound is labeled with a radiolabel selected from the group consisting of .sup.125I, .sup.3H, and a carbon-containing substituent as specified in claim 1, wherein at least one carbon is .sup.14C, b) separating the tissue-bound from the tissue-unbound radiolabeled compound of claim 1, c) quantifying the tissue-bound radiolabeled compound of claim 1, and d) converting the units of tissue-bound radiolabeled compound of claim 1 to units of micrograms of amyloid per 100 mg of tissue by comparison with a standard.
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