Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates
Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates
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DOI：
10.1021/jm010045q
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发表时间：
2001-06-07
影响因子：
7.3
通讯作者：
Kung, HF
中科院分区：
文献类型：
--
作者：
Zhuang, ZP;Kung, MP;Kung, HF
我们首次报道了基于放射性二化的小分子配体，显示出与A β聚集体的选择性结合，通过简单的扩散穿过完整的血脑屏障。研究人员开发了四种新型配体，它们对A β(1-40)和A β(1-42)肽的淀粉样蛋白聚集体具有优先标记性，而A β(1-40)和A β(1-42)肽通常与阿尔茨海默病（AD）患者大脑中的斑块有关。以较高的比活性（2200 Ci/mmol）制备了两个i -125标记的苯基苯（E，E）-1-碘-2,5-二（3-羟基羰基-4-羟基）-苯基苯，12 （ISB）和（E，E）-1-碘-2,5-二（3-羟基羰基-4-甲氧基）苯基苯，13 （IMSB）和两个i -125标记的硫黄素2-[4 '-（二甲氨基）苯基]-6-碘苯并噻唑，18a （TZDM）和2-[4 '-（4”-甲基哌嗪-1-基）苯基]-6-碘苯并噻唑，18b （TZPI）。这些配体的体外结合研究表明，A β聚集体（1-40）的K-d值分别为0.08、0.13、0.06和0.13 nM， A β聚集体（1-42）的K-d值分别为0.15、0.73、0.14和0.15 nM。有趣的是，在竞争结合分析条件下，在a β(1-40)和a β(1-42)聚集体上观察到不同的结合位点，这些位点相互排斥，用于苯基苯和硫黄素。对已知主要含有a - β(1-42)聚集物的唐氏综合征患者的死后脑切片进行放射自显影研究表明，[I-125]18a和[I-125]18b对这些脑切片进行了标记，但对a - β(1-40)聚集物选择性的[I-125]13对类似脑切片的标记非常低。正常小鼠静脉注射后的生物分布研究表明，[I-125]18a和[I-125]18b表现出良好的脑吸收和保留，其水平远高于[I-125]12和[I-125]13。这些发现强烈表明，新的放射性碘化配体[I-125]12 (ISB), [I-125]13 (IMSB), [I-125]18a, （TZDM）和[I-125]18b （TZPI）可能是研究AD患者淀粉样蛋白形成的A β(1-40)和A β(1-42)聚集物的有用生物标志物。
We report for the first time that small molecule-based radiodiodinated ligands, showing selective binding to A beta aggregates, cross the intact blood-brain barrier by simple diffusion. Four novel ligands showing preferential labeling of amyloid aggregates of A beta (1-40) and A beta (1-42) peptides, commonly associated with plaques in the brain of people with Alzheimer's disease (AD), were developed. Two I-125-labeled styrylbenzenes, (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-hydroxy)-styrylbenzene, 12 (ISB), and (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-methoxy)styrylbenzene, 13 (IMSB), and two I-125-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 K-d values of 0.08, 0.13, 0.06, and 0.13 nM for aggregates of A beta (1-40) and 0.15, 0.73, 0.14, and 0.15 nM for aggregates of A beta (1-42), respectively. Interestingly, under a competitive-binding assaying condition, different binding sites on A beta (1-40) and A beta (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 A beta (1-42) aggregates in the brain showed that both [I-125]18a and [I-125]18b labeled these brain sections, but [I-125]13, selective for A beta (1-40) aggregates, exhibited very low labeling of the comparable brain section. Biodistribution studies in normal mice after an iv injection showed that [I-125]18a and [I-125]18b exhibited excellent brain uptake and retention, the levels of which were much higher than those of [I-125]12 and [I-125]13. These findings strongly suggest that the new radioiodinated ligands, [I-125]12 (ISB), [I-125]13 (IMSB), [I-125]18a, (TZDM), and [I-125]18b (TZPI), may be useful as biomarkers for studying A beta (1-40) as well as A beta (1-42) aggregates of amyloidogenesis in AD patients.