title: Candidate anti-A beta fluorene compounds selected from analogs of amyloid imaging agents.
abstract: Alzheimer's disease (AD) is characterized by depositions of beta-amyloid (A beta) aggregates as amyloid in the brain. To facilitate diagnosis of AD by radioligand imaging, several highly specific small-molecule amyloid ligands have been developed. Because amyloid ligands display excellent pharmacokinetics properties and brain bioavailability, and because we have previously shown that some amyloid ligands bind the highly neurotoxic A beta oligomers (A beta O) with high affinities, they may also be valuable candidates for anti-A beta therapies. Here we identified two fluorene compounds from libraries of amyloid ligands, initially based on their ability to block cell death secondary to intracellular A beta O. We found that the lead fluorenes were able to reduce the amyloid burden including the levels of A beta O in cultured neurons and in 5xFAD mice. To explain these in vitro and in vivo effects, we found that the lead fluorenes bind and destabilize A beta O as shown by electron paramagnetic resonance spectroscopy studies, and block the harmful A beta O-synapse interaction. These fluorenes and future derivatives, therefore, have a potential use in AD therapy and research.
authors.affiliation: M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 2805 50th Street, Sacramento, CA 95817, USA,
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hong
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.forename: Madhu
authors.initials: M
authors.lastname: Budamagunta
authors.forename: Sandeep
authors.initials: S
authors.lastname: Rana
authors.forename: Aibin
authors.initials: A
authors.lastname: Shi
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: R Holland
authors.initials: RH
authors.lastname: Cheng
authors.forename: Duy H
authors.initials: DH
authors.lastname: Hua
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D000682:Amyloid / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000032:analysis* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004123:Dimethylamines / Q000737:chemistry / Q000627:therapeutic use; D005449:Fluorenes / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D004123:Dimethylamines; D005449:Fluorenes; C554365:K01 162; C554366:K01 186