Chalcone Analogue as New Candidate for Selective Detection of α-Synuclein Pathology
Chalcone Analogue as New Candidate for Selective Detection of α-Synuclein Pathology
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DOI：
10.1021/acschemneuro.1c00441
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发表时间：
2021-12-15
影响因子：
5
通讯作者：
Ono, Masahiro
中科院分区：
文献类型：
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作者：
Kaide, Sho;Watanabe, Hiroyuki;Ono, Masahiro
突触核蛋白（α -syn）聚集物的沉积是突触核蛋白病（包括帕金森病、路易体痴呆和多系统萎缩）的神经病理学标志之一。在体内用SPECT或PET检测α -syn聚集体可能是对抗突触核蛋白病的医学干预的有效工具。在本研究中，我们设计并合成了一系列具有不同芳基的查尔酮类似物，以评估它们作为α -syn成像探针的潜力。在竞争性抑制实验中，芳基显著影响了重组α -syn聚集体的结合亲和力和选择性。具有4-（二甲氨基）苯基的查尔酮类似物可与α -syn和β淀粉样蛋白（a β）结合，而具有4-硝基苯基的查尔酮类似物可与α -syn选择性结合。在荧光染色中，只有含有4-硝基苯基的查尔酮类似物成功地选择性检测了患者脑样品中人类α -syn对α - β聚集体的影响。其中，PHNP-3对α -syn聚集体的结合特性最有希望（K-i = 0.52 nM），值得进一步研究。然后进行I-125标记反应，得到[I-125]PHNP-3。在结合饱和度分析中，[I-125]PHNP-3以高亲和力（K-d = 6.9 nM）和选择性结合α -syn聚集体。在一项生物分布研究中，[I-125]PHNP-3在正常小鼠大脑中表现出适度的摄取（静脉注射后2分钟0.78% ID/g）。尽管其在脑内的药代动力学还有改进的空间，但本研究中令人鼓舞的体外结果表明，基于PHNP-3的进一步结构优化可能会导致未来开发出临床有用的靶向α -syn聚集体的探针。
Deposition of alpha-synuclein (alpha-syn) aggregates is one of the neuropathological hallmarks of synucleinopathies including Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. In vivo detection of alpha-syn aggregates with SPECT or PET may be an effective tool for medical intervention against synucleinopathy. In the present study, we designed and synthesized a series of chalcone analogues with different aryl groups to evaluate their potential as alpha-syn imaging probes. In competitive inhibition assays, aryl groups markedly affected binding affinity and selectivity for recombinant alpha-syn aggregates. Chalcone analogues with a 4-(dimethylamino)phenyl group bound to both alpha-syn and amyloid beta (A beta) aggregates while ones with a 4-nitrophenyl group displayed alpha-syn-selective binding. In fluorescent staining, only chalcone analogues with a 4-nitrophenyl group succeeded in selective detection of human alpha-syn against A beta aggregates in patients' brain samples. Among them, PHNP-3 exhibited the most promising binding characteristics for alpha-syn aggregates (K-i = 0.52 nM), encouraging us to further evaluate its utility. Then, a I-125-labeling reaction was performed to obtain [I-125]PHNP-3. In a binding saturation assay, [I-125]PHNP-3 bound to alpha-syn aggregates with high affinity (K-d = 6.9 nM) and selectivity. In a biodistribution study, [I-125]PHNP-3 exhibited modest uptake (0.78% ID/g at 2 min after intravenous injection) into a normal mouse brain. Although there is room for improvement of its pharmacokinetics in the brain, encouraging in vitro results in the present study indicate that further structural optimization based on PHNP-3 might lead to the development of a clinically useful probe targeting alpha-syn aggregates in the future.