Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque.
Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque.
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DOI：
10.1016/j.bmcl.2008.05.033
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发表时间：
2009-01
影响因子：
2.7
通讯作者：
S. Hausner;D. Alagille;A. Koren;L. Amici;J. Staley;K. Cosgrove;R. Baldwin;G. Tamagnan
中科院分区：
文献类型：
--
作者：
S. Hausner;D. Alagille;A. Koren;L. Amici;J. Staley;K. Cosgrove;R. Baldwin;G. Tamagnan
合成了一系列5-和6-取代的2-（4-二甲氨基苯基）-1，3-苯并恶唑类化合物，并对其作为阿尔茨海默病（AD）相关淀粉样斑块成像探针的潜力进行了体外和体内评价。其中几种化合物对Aβ1-40肽的体外结合亲和力在低纳摩尔范围内。发现N-（2-（4-（二甲氨基）苯基）-1，3-苯并恶唑-5-基）-4-碘苯甲酰胺（1 e）的Ki最低，为9.3nM。随后通过相应的三丁基甲锡烷基前体的碘去甲锡烷基化制备其123 I-放射性标记形式（[123 I] 1 e），并使用SPECT成像在狒狒模型中进行体内评价。与我们的预期相反，1 e没有在任何显著程度上穿过血脑屏障（BBB）。
A series of novel 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer’s Disease (AD)-related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Aβ1–40 peptide of several of these compounds were in the low-nanomolar range . The lowest Kiof 9.3nM was found for N-(2-(4-(dimethylamino)phenyl)-1,3-benzoxazol-5-yl)-4-iodobenzamide (1e). Its123I-radiolabeled form ([123I]1e) was subsequently prepared by iododestannylation of the corresponding tributylstannyl precursor and evaluated in vivo in a baboon model using SPECT imaging. Contrary to our expectations, 1e did not cross the blood–brain barrier (BBB) to any significant extent.