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

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, [¹⁸F]9a, exhibited a combination of high binding affinity to Aβ aggregates (K_i Combining double low line 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). [¹⁸F]9a clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [¹⁸F]9a did penetrate the intact BBB and specifically bind to Aβ plaques in vivo. Overall, [¹⁸F]9a may be a potential PET probe for imaging Aβ plaques in AD brains.