Blood-Brain Barrier Permeable 2-Phenylbenzothiazolyl Iridi-um Complexes as Inhibitors and Probes of Aβ Aggregation
ChemRxiv(2021)
摘要
The aggregation of amyloid β
(Aβ) peptides is a significant hallmark of Alzheimer’s Disease (AD) and the
inhibition and detection of Aβ aggregates are important for the treatment and
diagnosis of AD. Herein, a series of benzothiazole-based luminescent Ir(III)
complexes HN-1 to HN-8 were reported, which exhibit appreciable
Aβ aggregation inhibition ability in vitro and in living cells. In
addition, they are capable of inducing a fluorescence turn-on effect when binding
to Aβ fibrils and oligomers. Most importantly, compared to previously reported cationic
metal complexes, the neutral Ir complexes reported here show optimal Log D
values, which suggest these compounds should have enhanced blood brain barrier
(BBB) permeability. Most importantly, in vivo studies show that the neutral
Ir complexes HN-2, HN-3,
and HN-8 successfully penetrate the BBB and stain amyloid plaques in AD
mice brains after a 10-day treatment via i.p. injection, which is unprecedented
for Ir(III) complexes, and thus can be used as lead compounds
for AD therapeutics development.
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