Azure-A is one of the phenothiazines (PTZs) derivatives which for decades have been used as antipsychotic drugs due to good lipophilic characteristics which enable them to pass through the blood brain barrier (BBB), besides the important property of enabeling investigation of the pathological forms of aggregated tau protein found in the neurons of the central nervous system. Radioiodination of Azure-A was carried out via an electrophilic substitution reaction using chloramine-T as oxidizing agent. The influence of various reaction parameters and conditions on radioiodination efficiency was investigated and a high radiochemical yield of 92.07± 0.9 % was obtained. An in vitro cytotoxicity study of iodinated Azure-A on three cell lines (HCT-116, human colon carcinoma cell line; Hep-G2, liver carcinoma cell line and HFB-4, normal human melanocytes) was carried out and the data revealed that ioiodinated Azure A has no to very low toxic effect. The in vivo biodistribution study of 131 I-Azure A showed a high brain uptake of 6.15±0.09 % injected dose/g tissue organ at 30 min post-injection and its retention in brain remained high up to 2 h, whereas the clearance from the body appeared to proceed via the renal system. The experimental data were confirmed by the molecular docking studies to predict the effect of radioiodination on the binding affinity of the parent molecule (Azure A) to tau paired helical filaments (PHFs). Both ligands showed better binding to S2 and S3 pockets of (PHFs). Consequently, radioiodinated Azure A seems to be a good candidate as an imaging agent for taupathies such as Alzheimer's disease, Chronic traumatic encephalopathy, Corticobasal degeneration. Furthermore, it could be a very potent theranostics agent for brain tumors.

中文翻译：

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“通过放射性碘标记的 Azure A 靶向 Tau 蛋白用于脑治疗诊断：放射性标记、分子对接、体外和体内生物学评估”


Azure-A 是吩噻嗪 (PTZ) 衍生物之一，几十年来一直被用作抗精神病药物，因为它具有良好的亲脂特性，使其能够穿过血脑屏障 (BBB)，此外还具有促进病理学研究的重要特性。中枢神经系统神经元中发现的聚集 tau 蛋白的形式。使用氯胺-T 作为氧化剂，通过亲电取代反应进行 Azure-A 的放射性碘化。研究了各种反应参数和条件对放射性碘标记效率的影响，获得了92.07±0.9%的高放射化学产率。对碘化 Azure-A 对三种细胞系（HCT-116，人结肠癌细胞系；Hep-G2，肝癌细胞系和 HFB-4，正常人黑色素细胞）进行了体外细胞毒性研究，数据显示：碘化 Azure A 没有或非常低的毒性作用。 131 I-Azure A 的体内生物分布研究表明，注射后 30 分钟，脑摄取量为 6.15±0.09 % 注射剂量/g 组织器官，并且其在脑中的保留量在长达 2 小时内保持较高水平，而从身体似乎是通过肾脏系统进行的。实验数据经分子对接研究证实，可预测放射性碘标记对母体分子 (Azure A) 与 tau 配对螺旋丝 (PHF) 结合亲和力的影响。两种配体均表现出与 (PHF) 的 S2 和 S3 口袋更好的结合。因此，放射性碘化 Azure A 似乎是作为 tau 蛋白病（如阿尔茨海默氏病、慢性创伤性脑病、皮质基底节变性）显像剂的良好候选者。此外，它可能是一种非常有效的脑肿瘤治疗诊断剂。