Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Hubei Key Laboratory of Cell Homeostasis, State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
Eur J Med Chem. 2019 Sep 1;177:291-301. doi: 10.1016/j.ejmech.2019.05.065. Epub 2019 May 24.
Based on our previous research on the fluorinated phenylquinoxaline scaffold, in this study, different positions of N,N-dimethyl amino group, and alkyl linkers with various lengths were introduced into this scaffold to regulate their lipophilicity and binding affinity to Tau. Four novel Tc/Re complexes with diethyl iminodiacetate chelator were synthesized and evaluated as Tau imaging tracers in the brain of Alzheimer's disease. Their specific binding to neurofibrillary tangles was verified by in vitro fluorescence staining and further confirmed by the results of immunofluorescence staining on the same brain sections from AD patient and Tg-tau mice. From in vitro binding assay using recombinant Tau aggregates, complex 4.2 with 6-N(CH) and longer carbon chain (n = 4) displayed the highest affinity (K = 59.95 nM). [Tc]4.2 was achieved by the ligand exchange reaction between dicarboxylic precursor and [Tc(CO)(HO)] intermediate with radiochemical yield over 45%. Ex vivo biodistribution studies on normal ICR mice revealed that [Tc]4.2 exhibited moderate initial brain uptake (0.61% ID/g) and more structure optimizations are still required to improve the blood-brain barrier permeability.
基于我们之前对氟苯基喹喔啉支架的研究，在本研究中，在该支架中引入了不同位置的 N,N-二甲基氨基和不同长度的烷基连接体，以调节其亲脂性和与 Tau 的结合亲和力。我们合成了四个具有二乙基乙二胺五乙酸螯合剂的新型 Tc/Re 配合物，并将其作为 Tau 成像示踪剂在阿尔茨海默病患者的大脑中进行了评估。通过体外荧光染色验证了它们对神经纤维缠结的特异性结合，并通过对 AD 患者和 Tg-tau 小鼠相同脑切片的免疫荧光染色结果进一步证实。从使用重组 Tau 聚集体的体外结合测定中，具有 6-N(CH)和更长碳链 (n = 4) 的复合物 4.2 显示出最高的亲和力 (K = 59.95 nM)。[Tc]4.2 通过二羧酸前体与[Tc(CO)(HO)]中间体之间的配体交换反应合成，放射化学产率超过 45%。在正常 ICR 小鼠的离体生物分布研究中，[Tc]4.2 表现出中等的初始脑摄取（0.61% ID/g），仍需要进一步的结构优化来提高血脑屏障通透性。
