Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing 100875, China.
Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing 100853, China.
Mol Pharm. 2021 Mar 1;18(3):1176-1195. doi: 10.1021/acs.molpharmaceut.0c01078. Epub 2021 Jan 21.
In this study, three pairs of optically pure F-labeled 2-phenylquinoxaline derivatives were evaluated as Tau imaging agents for the diagnosis of Alzheimer's disease (AD). The chiral 2-fluoromethyl-1,2-ethylenediol side chain was attached to the 2-phenylquinoxaline backbone to increase hydrophilicity, thereby improving the binding affinity of the probe to tangles and their selectivity toward Tau tangles over β-amyloid plaques (Aβ). These probes displayed excellent fluorescent properties and high selectivity for tangles on brain sections from transgenic mice (rTg4510) and AD patients. Quantitative binding assays with AD homogenates showed that the probes and have a high affinity ( = 4.1 and 10.3 nM, respectively) and high selectivity (30.5-fold and 34.6-fold, respectively) for tangles over Aβ. The high affinity and selectivity of and for tangles were further confirmed with autoradiography on AD brain tissue in vitro. In addition, they displayed sufficient blood-brain barrier penetration (7.06% and 10.95% ID/g, respectively) and suitable brain kinetics (brain/brain = 10.1, 6.5 respectively) in normal mice. Ex vivo metabolism studies and micro-positron emission computed tomography (PET) revealed high brain biostability, good brain kinetic properties, and low nonspecific binding for . Together, these results demonstrate that and are promising PET probes for Tau tangles imaging.
在这项研究中，三对光学纯的 F 标记的 2-苯基喹喔啉衍生物被评估为用于阿尔茨海默病（AD）诊断的 Tau 成像剂。手性 2-氟甲基-1,2-乙二醇侧链连接到 2-苯基喹喔啉骨架上，以增加亲水性，从而提高探针与缠结的结合亲和力及其对 Tau 缠结相对于 β-淀粉样斑块（Aβ）的选择性。这些探针在转基因小鼠（rTg4510）和 AD 患者的脑切片上显示出优异的荧光性质和对缠结的高选择性。与 AD 匀浆进行的定量结合测定表明，探针 和 对缠结具有高亲和力（分别为 4.1 和 10.3 nM）和高选择性（分别为 30.5 倍和 34.6 倍）。在体外 AD 脑组织的放射自显影中进一步证实了 和 对缠结的高亲和力和选择性。此外，它们在正常小鼠中表现出足够的血脑屏障穿透性（分别为 7.06%和 10.95%ID/g）和合适的脑动力学（脑/脑 = 10.1、6.5）。离体代谢研究和微正电子发射计算机断层扫描（PET）揭示了 具有高脑生物稳定性、良好的脑动力学特性和低非特异性结合。综上所述，这些结果表明 和 是有前途的 Tau 缠结成像的 PET 探针。
