While the etiology of non-familial Parkinson’s disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We, therefore, designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10–20 µM blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP⁺) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). Rescue was also observed when chelators were given after the toxicant. SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly support the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation.

尽管尚不清楚非家族性帕金森氏病（PD）的病因，但有证据表明组织铁水平的升高可能是一个促成因素。而且，暴露于一些环境毒物被认为是另外的危险因素。因此，以脑为靶的铁螯合剂作为多巴胺能中毒的解毒剂和PD的潜在治疗方法是令人感兴趣的。因此，我们设计了一系列对三价铁具有高亲和力的小分子，并包含一些结构元素，以允许它们通过中性氨基酸转运蛋白LAT1（SLC7A5）转运至大脑。合成了五个候选分子，并初步对其进行了表征，以保护其免受人类神经元的铁锈病的侵害。有希望的羟基吡啶酮酮SK4被进一步表征。证实了在pH值的生理范围内的选择性铁螯合和LAT1的摄取。浓度为10–20 µM的物质可阻止由帕金森氏神经毒物甲基苯基吡啶（MPP）触发的神经突丢失和细胞死亡。⁺）和人多巴胺能神经元培养物（LUHMES细胞）中的6-羟基多巴胺（6-OHDA）。当毒药后给予螯合剂时，也观察到了抢救。缺乏LAT1亲和力或铁螯合能力降低的SK4衍生物在我们的检测组中显示出预期的活性改变。因此，开发了一种铁螯合剂，该螯合剂具有神经保护特性，如在几种模型中评估的那样。数据强烈支持铁在多巴胺能神经毒性中的作用，并建议对改善脑铁螯合的拟议设计策略进行进一步探索。