Blood-Brain Barrier Permeable 2-Phenylbenzothiazolyl Iridi-um Complexes as Inhibitors and Probes of Aβ Aggregation

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.