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 [¹²⁵I]­BOB-4 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 (K_i = 15.8–45.0 nM) for Aβ_1–42 aggregates, and (R)-enantiomers showed slightly better binding ability than (S)-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 ¹²⁵I-radiolabeled enantiomers, (S)-[¹²⁵I]5 and (R)-[¹²⁵I]5, specific plaque labeling on brain sections of Tg mice and AD patients were observed in in vitro autoradiography, persuasively proving the excellent affinity of the probes. In biodistribution, (S)-[¹²⁵I]5 and (R)-[¹²⁵I]5 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_2min/brain_60min = 19.0 and 17.7, respectively). In summary, the separate enantiomers displayed similar properties in vitro and in vivo, and (S/R)-[¹²³I]5 may be potential SPECT probes for recognizing Aβ plaques in AD brains.