%0 Journal Article
%A Jia, Jianhua
%A Song, Jia
%A Dai, Jiapei
%A Liu, Boli
%A Cui, Mengchao
%D 2016
%T Optically Pure Diphenoxy Derivatives as More Flexible
Probes for β‑Amyloid Plaques
%U https://acs.figshare.com/articles/journal_contribution/Optically_Pure_Diphenoxy_Derivatives_as_More_Flexible_Probes_for_Amyloid_Plaques/3479312
%R 10.1021/acschemneuro.6b00155.s001
%2 https://acs.figshare.com/ndownloader/files/5489864
%K Optically Pure Diphenoxy Derivatives
%K IMPY
%K AD brains
%K diphenoxy derivatives
%K 125 I-radiolabeled enantiomers
%K competition binding assay
%K min
%K β binding probes
%K ID
%K SPECT
%X 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
(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.
%I ACS Publications