Optically Pure Diphenoxy Derivatives as More Flexible Probes for β‑Amyloid Plaques

The highly rigid and planar scaffold with π-conjugated systems has been widely considered to be indispensable for Aβ binding probes. However, the flexible benzyloxybenzene derivative [<sup>125</sup>I]­BOB-<b>4</b> represents an excellent lead candidate for targeting Aβ in AD brains. Based on that, we designed two pairs of more flexible and optically pure diphenoxy derivatives with a chiral center as novel Aβ probes. These compounds possessed high affinity (<i>K</i><sub>i</sub> = 15.8–45.0 nM) for Aβ<sub>1–42</sub> aggregates, and (<i>R</i>)-enantiomers showed slightly better binding ability than (<i>S</i>)-enantiomers. In addition, the competition binding assay implied that the optically pure diphenoxy derivatives with more flexible geometry shared the same binding site as IMPY, a classical rigid and planar Aβ probe. For <sup>125</sup>I-radiolabeled enantiomers, (<i>S</i>)-[<sup>125</sup>I]<b>5</b> and (<i>R</i>)<b>-</b>[<sup>125</sup>I]<b>5</b>, specific plaque labeling on brain sections of Tg mice and AD patients were observed in <i>in vitro</i> autoradiography, persuasively proving the excellent affinity of the probes. In biodistribution, (<i>S</i>)-[<sup>125</sup>I]<b>5</b> and (<i>R</i>)<b>-</b>[<sup>125</sup>I]<b>5</b> with relatively low lipophilicity exhibited moderate initial brain uptake (4.37% and 3.72% ID/g at 2 min, respectively) and extremely fast washout from normal mice brain (brain<sub>2min</sub>/brain<sub>60min</sub> = 19.0 and 17.7, respectively). In summary, the separate enantiomers displayed similar properties <i>in vitro</i> and <i>in vivo</i>, and (<i>S</i>/<i>R</i>)-[<sup>123</sup>I]<b>5</b> may be potential SPECT probes for recognizing Aβ plaques in AD brains.