354817-19-9Relevant articles and documents
Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates
Zhuang,Kung,Hou,Skovronsky,Gur,Pl?ssl,Trojanowski,Lee,Kung
, p. 1905 - 1914 (2001)
We report for the first time that small molecule-based radiodiodinated ligands, showing selective binding to Aβ aggregates, cross the intact blood-brain barrier by simple diffusion. Four novel ligands showing preferential labeling of amyloid aggregates of Aβ(1-40) and Aβ(1-42) peptides, commonly associated with plaques in the brain of people with Alzheimer's disease (AD), were developed. Two 125I-labeled styrylbenzenes, (E,E)-1-iodo-2,5-bis(3-hydroxvcarbonyl-4-hydroxy)-styrylbenzene, 12 (ISB), and (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-methoxy)styrylbenzene, 13 (IMSB), and two 125I-labeled thioflavins, 2-[4′-(dimethylamino)phenyl]-6-iodobenzothiazole, 18a (TZDM), and 2-[4′-(4″-methylpiperazin-1-yl)phenyl]-6-iodobenzothiazole, 18b (TZPI), were prepared at a high specific activity (2200 Ci/mmol). In vitro binding studies of these ligands showed excellent binding affinities with Kd values of 0.08, 0.13, 0.06, and 0.13 nM for aggregates of Aβ(1-40) and 0.15, 0.73, 0.14, and 0.15 nM for aggregates of Aβ(1-42), respectively. Interestingly, under a competitive-binding assaying condition, different binding sites on Aβ(1-40) and Aβ(1-42) aggregates, which are mutually exclusive, were observed for styrylbenzenes and thioflavins. Autoradiography studies of postmortem brain sections of a patient with Down's syndrome known to contain primarily Aβ(1-42) aggregates in the brain showed that both [125I]18a and [125I]18b labeled these brain sections, but [125I] 13, selective for Aβ(1-40) aggregates, exhibited very low labeling of the comparable brain section. Biodistribution studies in normal mice after an iv injection showed that [125I]18a and [125I]18b exhibited excellent brain uptake and retention, the levels of which were much higher than those of [125I]12 and [125I]13. These findings strongly suggest that the new radioiodinated ligands, [125I]12 (ISB), [125I]13 (IMSB), [125I]18a (TZDM), and [125I]18b (TZPI), may be useful as biomarkers for studying Aβ(1-40) as well as Aβ(1-42) aggregates of amyloidogenesis in AD patients.
Isomerization of (Z,Z) to (E,E)1-bromo-2,5-bis-(3- hydroxycarbonyl-4-hydroxy)-styrylbenzene in strong base: Probes for amyloid plaques in the brain
Lee,Zhuang,Kung,Pl?ssl,Skovronsky,Gur,Hou,Trojanowski,Lee,Kung
, p. 2270 - 2275 (2007/10/03)
In developing probes for detecting β-amyloid (Aβ) plaques in the brain of Alzheimer's disease (AD), we have synthesized 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (5, BSB). Due to the presence of two double bonds, formation of four different isomers is possible. Four isomers, E,E-5, E,Z-5, Z,E-5, and Z,Z-5, were prepared. Surprisingly, all showed strong fluorescent labeling of Aβ plaques in the brain of postmortem brain sections of patients with confirmed AD. In vitro binding assay also showed that all four isomers of BSB (E,E-5, E,Z-5, Z,E-5, and Z,Z-5) displayed a similar high binding affinity inhibiting the binding of [125I] E,E-6, 1-iodo-2,5-bis-(3-hydroxycarbonyl-4-methoxy)styrylbenzene (IMSB) to Aβ1-40 aggregates. The inhibition constants (Ki) of EE-5, EZ-5, ZE-5, and Z,Z-5 were 0.11 ± 0.01, 0.19 ± 0.03, 0.27 ± 0.06, and 0.13 ± 0.02 nM, respectively. Due to the fact that geometric stability of these styrylbenzenes is unknown, and the conversion of Z,Z-5 to E,E-5 may occur automatically in the binding or labeling assaying conditions, we have investigated the kinetics of conversion of Z,Z-5 to E,E-5 by NMR in D2O/NaOD at elevated temperatures (70, 95, and 115 °C). The activation energy was determined to be 14.15 kcal/mol. The results strongly suggest that the isomeric conversion at room temperature in aqueous buffer solution is unlikely. All of the styrylbenzene isomers clearly showed potential as useful tools for studying Aβ aggregates in the brain. The data suggest that, despite the rigidity of this series of styrylbenzenes, the binding sites on Aβ aggregates may have certain flexibility and the binding pockets could be adaptable for binding to other smaller ligands. Such information could be exploited to develop new ligands for detecting amyloid plaques in AD.
