Synthesis and Bioevaluation of 2-Styrylquinoxaline Derivatives as Tau-PET Tracers
Nan Wu, Longfei Zhang, Xiaojun Zhang, Qi‐Lei Zhang, Jiaqi Liu, Yuying Li, Xiao‐Xin Yan, Yi Liang, Jinming Zhang, Mengchao Cui
Abstract
This study focused on designing and evaluating Tau-PET tracers for noninvasive positron emission computed tomography (PET) imaging of neurofibrillary tangles (NFTs), a hallmark pathology of Alzheimer’s disease (AD). The tracers were synthesized with a 2-styrylquinoxaline scaffold and varying lengths of FPEG chains. The compound [ 18 F] 15, which had two ethoxy units, showed high affinity for recombinant K18-Tau aggregates ( K i = 41.48 nM) and the highest selectivity versus Aβ 1–42 aggregates (8.83-fold). In vitro autoradiography and fluorescent staining profiles further validated the binding of [ 18 F] 15 or 15 toward NFTs in brain sections from AD patients and Tau-transgenic mice. In normal ICR mice, [ 18 F] 15 exhibited an ideal initial brain uptake (11.21% ID/g at 2 min) and moderate washout ratio (2.29), and micro-PET studies in rats confirmed its ability to penetrate the blood–brain barrier with the peak SUV value of 1.94 in the cortex. These results suggest that [ 18 F] 15 has the potential to be developed into a useful Tau-PET tracer for early AD diagnosis and evaluation of anti-Tau therapeutics.