PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) is a small Cu(II)-binding drug that has been investigated in the treatment of neurodegenerative diseases, namely, Alzheimer’s disease (AD). PBT2 is thought to be highly effective at crossing the blood–brain barrier and has been proposed to exert anti-Alzheimer’s effects through the modulation of metal ion concentrations in the brain, specifically the sequestration of Cu(II) from amyloid plaques. However, despite promising initial results in animal models and in clinical trials where PBT2 was shown to improve cognitive function, larger-scale clinical trials did not find PBT2 to have a significant effect on the amyloid plaque burden compared with controls. We propose that the results of these clinical trials likely point to a more complex mechanism of action for PBT2 other than simple Cu(II) sequestration. To this end, herein we have investigated the solution chemistry of Cu(II) coordination by PBT2 primarily using X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS, and electron paramagnetic resonance. We propose that a novel bis-PBT2 Cu(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu(II)-bis-PBT2 complex distorted from coplanarity. Additionally, PBT2 is a more flexible ligand than other 8HQs because it can act as both a bidentate and a tridentate ligand as well as coordinate Cu(II) in both 1:1 and 2:1 PBT2/Cu(II) complexes.

中文翻译：

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铜（II）与PBT2的结合不同于其他8-羟基喹啉螯合剂：对神经退行性蛋白质错误折叠疾病的治疗意义。

PBT2（5,7-二氯-2-[（（二甲氨基）甲基] -8-羟基喹啉）是一种小的Cu（II）结合药物，已被用于治疗神经退行性疾病，即阿尔茨海默氏病（AD）。人们认为PBT2在穿越血脑屏障方面非常有效，并且已提出通过调节大脑中金属离子的浓度，特别是从淀粉样蛋白斑块中分离Cu（II）来发挥抗阿尔茨海默氏病的作用。然而，尽管在动物模型和临床试验中有希望的初步结果表明PBT2可以改善认知功能，但大规模临床试验并未发现PBT2对淀粉样斑块的负担与对照组相比有显着影响。我们建议这些临床试验的结果可能表明PBT2的作用机制比简单的Cu（II）隔离更为复杂。为此，本文中我们主要使用X射线吸收光谱（XAS），高能分辨荧光检测XAS和电子顺磁共振研究了PBT2对Cu（II）配位的溶液化学。我们提议一本小说双-PBT2铜（II）配合物与非对称配位在溶液中可以共存用对称四配位的Cu（II） -双-PBT2复杂从共面扭曲。此外，PBT2是比其他8HQ更灵活的配体，因为它既可以充当二齿和三齿配体，又可以在1：1和2：1 PBT2 / Cu（II）络合物中配位Cu（II）。