Preliminary evaluation of fluoro-pegylated benzyloxybenzenes for quantification of β-amyloid plaques by positron emission tomography

• DOI: 10.1016/j.ejmech.2015.09.028
• Publication Date: 2015-09-26T14:52:56Z
• Authors: Yanping Yang; Hualong Fu; Mengchao Cui; Cheng Peng; Zhigang Liang; Jiapei Dai; Zhiyong Zhang; Chunping Lin; Boli Liu
• Keywords: 0301 basic medicine; Mice, Inbred ICR; Amyloid beta-Peptides; Molecular Structure; Brain; Mice, Transgenic; Plaque, Amyloid; 3. Good health; Mice, Inbred C57BL; Molecular Docking Simulation; Mice; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; 13. Climate action; Molecular Probes; Positron-Emission Tomography; Benzene Derivatives; Animals; Autoradiography; Humans

A new series of fluoro-pegylated benzyloxybenzenes were designed, synthesized and evaluated as PET probes for early detection of Aβ plaques. Molecular docking revealed that all of the flexible benzyloxybenzenes inserted themselves into the hydrophobic Val18_Phe20 cleft on the flat spine of the Aβ fiber, in a manner similar to that of IMPY molecule. The most potent probe, [(18)F]9a, exhibited a combination of high binding affinity to Aβ aggregates (Ki = 21.0 ± 4.9 nM), high initial brain uptake (9.14% ID/g at 2 min), fast clearance from normal brain tissue (1.79% ID/g at 60 min), and satisfactory in vivo biostability in the brain (95% of intact form at 2 min). [(18)F]9a clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [(18)F]9a did penetrate the intact BBB and specifically bind to Aβ plaques in vivo. Overall, [(18)F]9a may be a potential PET probe for imaging Aβ plaques in AD brains.