cn6b00155_si_001.pdf (3.41 MB)
Optically Pure Diphenoxy Derivatives as More Flexible Probes for β‑Amyloid Plaques
Version 2 2016-07-11, 14:05
Version 1 2016-07-11, 13:04
journal contribution
posted on 2016-06-23, 00:00 authored by Jianhua Jia, Jia Song, Jiapei Dai, Boli Liu, Mengchao CuiThe 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
(Ki = 15.8–45.0 nM) for Aβ1–42 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 (brain2min/brain60min = 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.