title: Lipophilic analogs of thioflavin S as novel amyloid-imaging agents.
abstract: Lipophilic analogs of thioflavin S were synthesized and radiolabeled with positron or single photon emitting radionuclides. The binding affinity for Abeta was evaluated using isolated amyloid fibrils from human brain tissue. Binding specificity was assessed using fluorescent tissue staining. In vivo brain uptake was evaluated in mice. Following synthesis, neutral analogs of thioflavin S capable of radiolabeling with (11)C or (125)I, were found to bind isolated human Abeta with affinities in the nanomolar range. Fluorescent tissue staining showed selective binding to Abeta deposits in vitro. Biodistribution of selected compounds displayed high brain permeability at early time points. At later points, the compounds were cleared from the normal brain, indicating low non-specific binding in vivo. These studies indicated that novel amyloid imaging probes can be developed based on thioflavin S that readily entered the brain and selectively bound to Abeta deposits and neurofibrilary tangles. Potential applications of these amyloid binding agents include facilitating drug screening in animal models and use as in vivo markers of early and definitive diagnosis of AD.
authors.affiliation: College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Wu
authors.forename: Lisheng
authors.initials: L
authors.lastname: Cai
authors.forename: Jingjun
authors.initials: J
authors.lastname: Wei
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000345:Affinity Labels / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D001667:Binding, Competitive; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D003952:Diagnostic Imaging / Q000379:methods; D004353:Drug Evaluation, Preclinical; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D015394:Molecular Structure; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging; D011485:Protein Binding; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000345:Affinity Labels; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D002250:Carbon Radioisotopes; D005456:Fluorescent Dyes; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D013844:Thiazoles; C009462:thioflavin T