346691-90-5Relevant 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 (2007/10/03)
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.
