Thioflavin derivatives for use in the antemortem diagnosis of Alzheimers disease and in vivo imaging and prevention of amyloid deposition

An amyloid binding compound of the following formula or a water soluble, non-toxic salt thereof:

• 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:
• Y is NR1R2, OR2, or SR2;
• wherein the nitrogen of
• is not a quaternary amine;
• each R1 and R2 independently is selected from the group consisting of H, a lower alkyl group, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, CH2—CH2—CH2X (wherein X═F, Cl, Br or I), (C═O)—R′, Rph, and (CH2)nRph (wherein n=1, 2, 3, or 4 and Rph represents an unsubstituted or substituted phenyl group, wherein substituents of Rph are selected from the group consisting of F, Cl, Br, I, a lower alkyl group, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2—CH2X (wherein X═F, Cl, Br or I), CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)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—, —CH2O— and —CH2NH—;
• W is —(CH2), where n=0,1,2,3,4, or 5;
• and L is:
• wherein M is selected from the group consisting of Tc and Re;
• and R′ is H or a lower alkyl group);
• each R3-R10 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2—CH2X (wherein X═F, Cl, Br or I), CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph, CR2′—CR2′-Rph (wherein Rph 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—, —CH2O— and —CH2NH—;
• W is —CH2)n where n=0,1,2,3,4, or 5;
• and L is:
• wherein M is selected from the group consisting of Tc and Re;
• or each R1 and R2 is a chelating group (with or without a chelated metal group) of the form W-L, wherein W is —CH2)n where n=2,3,4, or 5;
• and L is:
• wherein M is selected from the group consisting of Tc and Re;
• or wherein each R3-R10 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 —CH2)n where n=0,1,2,3,4, or 5;
• L is:
• and wherein R15 independently is selected from the following:
• or an amyloid binding, chelating compound (with or without a chelated metal group) or a water soluble, non-toxic salt thereof of the form:
• wherein R15 independently is selected from the following:
• and R16 is
• wherein Q is independently selected from one of the following structures:
• Z is S, NR′, O, or C(R′)2 in which R′ is H or a lower alkyl group;
• U is N or CR′;
• Y is NR1R2, OR2, or SR2;
• each R17-R24 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2—CH2X (wherein X═F, Cl, Br or I), CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph and CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group and wherein R′ is H or a lower alkyl group);
• wherein at least one of the substituents R1-R10 is selected from the group consisting of 3H, 131I, 125I, 123I, 76Br, 75Br, 18F, CH2—CH2—X*, O—CH2—CH2—X*, CH2—CH2—CH2—X*, O—CH2—CH2—CH2—X* (wherein X*=131I, 123I, 76Br, 75Br or 18F), 19F, 125I, a carbon-containing substituent selected from the group consisting of lower alkyl, (CH2)nOR′, CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2—CH2X (wherein X═F, Cl, Br or I), CN, (C═O)—R′, (C═O)N(R′)2, O(CO)R′, COOR′, CR′═CR′—Rph and CR2′-CR2′-Rph wherein at least one carbon is 11C, 13C or 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—, —CH2O— and —CH2NH—;
• W is —(CH2), where n=0,1,2,3,4, or 5;
• and L* is:
• wherein M* is 99mTc;
• or L* is:
• and wherein R15 independently is selected from the following:
• or a chelating compound (with chelated metal group) of the form:
• wherein R15 independently is selected from the following:
• and R16 is
• wherein Q is independently selected from one of the following structures:
• Z is S, NR′, O, or C(R′)2 in which R′ is H or a lower alkyl group;
• U is N or CR′;
• Y is NR1R2, OR2, or SR2;
• wherein each R17—R24 independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH2)nOR′ (wherein n=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2—CH2X (wherein X═F, Cl, Br or I), CN, (C═O)—R′, N(R′)2, NO2, (C═O)N(R′)2, O(CO)R′, OR′, SR′, COOR′, Rph, CR′═CR′—Rph and CR2′—CR2′—Rph (wherein Rph represents an unsubstituted or substituted phenyl group and wherein R′ is H or a lower alkyl group).