title: Styrylbenzoazole derivatives for imaging of prion plaques and treatment of transmissible spongiform encephalopathies.
abstract: Recent prevalence of acquired forms of transmissible spongiform encephalopathies (TSEs) has urged the development of early diagnostic measures as well as therapeutic interventions. To extend our previous findings on the value of amyloid imaging probes for these purposes, styrylbenzoazole derivatives with better permeability of blood-brain barrier (BBB) were developed and analyzed in this study. The new styrylbenzoazole compounds clearly labeled prion protein (PrP) plaques in brain specimens from human TSE in a manner irrespective of pathogen strain, and a representative compound BF-168 detected abnormal PrP aggregates in the brain of TSE-infected mice when the probe was injected intravenously. On the other hand, most of the compounds inhibited abnormal PrP formation in TSE-infected cells with IC50 values in the nanomolar range, indicating that they represent one of the most potent classes of inhibitor ever reported. BF-168 prolonged the lives of mice infected intracerebrally with TSE when the compound was given intravenously at the preclinical stage. The new compounds, however, failed to detect synaptic PrP deposition and to show pathogen-independent therapeutic efficacy, similar to the amyloid imaging probes we previously reported. The compounds were BBB permeable and non-toxic at doses for imaging and treatment; therefore, they are expected to be of practical use in human TSE.
authors.affiliation: Division of Prion Biology, Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai, Japan. ishikawa@mail.tains.tohoku.ac.jp
authors.forename: Kensuke
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Yukitsuka
authors.initials: Y
authors.lastname: Kudo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suemoto
authors.forename: Tohru
authors.initials: T
authors.lastname: Sawada
authors.forename: Toru
authors.initials: T
authors.lastname: Iwaki
authors.forename: Katsumi
authors.initials: K
authors.lastname: Doh-ura
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D006224:Cricetinae; D004195:Disease Models, Animal; D007202:Indicators and Reagents; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D017096:Prion Diseases / Q000188:drug therapy* / Q000635:transmission; D011328:Prions / Q000302:isolation & purification / Q000648:ultrastructure*; D013343:Styrenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D007202:Indicators and Reagents; D011328:Prions; D013343:Styrenes; D013844:Thiazoles