Li Yuyan, Yang Jian, Liu Hongwu, Yang Jing, Du Lei, Feng Haiwei, Tian Yanli, Cao Jianqin, Ran Chongzhao
Molecular Imaging Laboratory , MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging , Department of Radiology , Massachusetts General Hospital/Harvard Medical School , Charlestown , Massachusetts 02129 , USA.
School of Pharmacy , China Pharmaceutical University , Nanjing , 210009 , China.
Chem Sci. 2017 Nov 1;8(11):7710-7717. doi: 10.1039/c7sc02050c. Epub 2017 Sep 15.
Amyloid peptides and proteins are associated with the pathologies of numerous diseases. In the progression of a disease, amyloids exist in soluble and insoluble forms, which are the dominant species at different stages of the disease and they have different degrees of toxicity. However, differentiating between the soluble and insoluble forms is very challenging with small molecule probes due to multiple obstacles that need to be overcome. Inspired by the recognition principle of antibodies for sAβ, we hypothesized that the accessibility/tightness of soluble and insoluble amyloids could be utilized to design imaging probes to recognize different amyloid forms and the stereo-hindrance tuning strategy could be used to design imaging probes for selectively detecting the soluble amyloid beta (sAβ) species in Alzheimer's disease (AD). Herein, we demonstrated that tuning the stereo-hindrance of the phenoxy-alkyl chains at the 4-position of a curcumin scaffold could lead to certain selectivity for sAβ over insoluble Aβs (insAβ). Among the designed compounds, showed a 68-fold higher affinity for sAβ than for insAβ (7.5 ± 10 nM 505.9 ± 275.9 nM). Moreover, our imaging data indicated that was indeed capable of detecting sAβ using 4 month old APP/PS1 mice, in which sAβ is the predominant species in the brain. In addition, we also demonstrated that could be used to monitor the increase in sAβ loading from the ages of 4 months old to 12 months old. We believe that can be a useful probe for selectively detecting sAβ species in AD and that our probe designing strategy can be applied to other amyloids and will have tremendous impact on AD drug development and other amyloid research.
淀粉样肽和蛋白质与多种疾病的病理过程相关。在疾病进展过程中，淀粉样蛋白以可溶和不可溶形式存在，它们在疾病的不同阶段占主导地位，且具有不同程度的毒性。然而，由于需要克服多个障碍，使用小分子探针区分可溶和不可溶形式极具挑战性。受抗体对可溶性淀粉样β蛋白（sAβ）识别原理的启发，我们推测可利用可溶性和不可溶性淀粉样蛋白的可及性/紧密性来设计成像探针，以识别不同的淀粉样蛋白形式，并且可采用立体位阻调节策略来设计成像探针，用于选择性检测阿尔茨海默病（AD）中的可溶性淀粉样β蛋白（sAβ）。在此，我们证明了调节姜黄素支架4位苯氧基烷基链的立体位阻可导致对sAβ相对于不可溶性Aβ（insAβ）具有一定的选择性。在所设计的化合物中，[具体化合物名称未给出]对sAβ的亲和力比对insAβ高68倍（7.5±1.0 nM对505.9±275.9 nM）。此外，我们的成像数据表明，[具体化合物名称未给出]确实能够使用4月龄的APP/PS1小鼠检测sAβ，在这些小鼠的大脑中sAβ是主要形式。此外，我们还证明了[具体化合物名称未给出]可用于监测从4月龄到12月龄sAβ负荷的增加。我们相信，[具体化合物名称未给出]可成为选择性检测AD中sAβ的有用探针，并且我们的探针设计策略可应用于其他淀粉样蛋白，将对AD药物开发和其他淀粉样蛋白研究产生巨大影响。
