Discovery and evaluation of aza-fused tricyclic derivatives for detection of Tau pathology in Alzheimer's disease

• Published in: European journal of medicinal chemistry Vol. 246; p. 114991
• Main Authors: Liu, Tianqing, Li, Yuying, Wang, Yan, Yan, Xiao-Xin, Dai, Jiapei, Cui, Mengchao
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.01.2023
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Autoradiography; Brain - metabolism; Humans; Monoamine Oxidase - metabolism; Neurofibrillary Tangles - metabolism; Positron-Emission Tomography; Radiotracer; tau Proteins - metabolism; Tau tangles; Autoradiography; Alzheimer's disease; Radiotracer; Tau tangles
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114991

For various neurodegenerative diseases, including Alzheimer's disease (AD), the abnormal aggregation of Tau is not only the predominant contributing factor but also a major biomarker for disease diagnosis. In this study, a series of aza-fused tricyclic derivatives were designed and synthesized. By changing the position and number of nitrogen atoms on the fused tricyclic core, the imidazonaphthyridine scaffold was screened and reported for the first time which could potentially detect Tau aggregates. Through a series of in vitro and in vivo biological evaluations, probe [125I]5 possessed exceptional binding affinity (IC50 = 1.63 nM) to neurofibrillary tangles in the AD brain, high selectivity over Aβ plaques (23.4-fold), clean off-target profile to monoamine oxidase A/B (MAO-A/B), and suitable pharmacokinetics (initial brain uptake = 3.22% ID/g). [Display omitted] •Aza-fused tricyclic derivatives were discovered as Tau binding scaffold.•[125I]5 possessed high binding affinity to Tau, high selectivity for Aβ plaques.•[125I]5 displayed clean off-target profile to monoamine oxidase A/B.•[125I]5 displayed suitable pharmacokinetics in mice.