title: Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts.
abstract: The receptor for advanced glycation endproducts (RAGE) is a 35 kDa transmembrane receptor that belongs to the immunoglobulin superfamily of cell surface molecules. Its role in Alzheimer's disease (AD) is complex, but it is thought to mediate influx of circulating amyloid-β into the brain as well as amplify Aβ-induced pathogenic responses. RAGE is therefore of considerable interest as both a diagnostic and a therapeutic target in AD. Herein we report the synthesis and preliminary preclinical evaluation of [(18)F]RAGER, the first small molecule PET radiotracer for RAGE (Kd = 15 nM). Docking studies proposed a likely binding interaction between RAGE and RAGER, [(18)F]RAGER autoradiography showed colocalization with RAGE identified by immunohistochemistry in AD brain samples, and [(18)F]RAGER microPET confirmed CNS penetration and increased uptake in areas of the brain known to express RAGE. This first generation radiotracer represents initial proof-of-concept and a promising first step toward quantifying CNS RAGE activity using PET. However, there were high levels of nonspecific [(18)F]RAGER binding in vitro, likely due to its high log P (experimental log P = 3.5), and rapid metabolism of [(18)F]RAGER in rat liver microsome studies. Therefore, development of second generation ligands with improved imaging properties would be advantageous prior to anticipated translation into clinical PET imaging studies.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Cary
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Allen F
authors.initials: AF
authors.lastname: Brooks
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.|The Interdepartmental Program in Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Fawaz
authors.affiliation: The Interdepartmental Program in Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Drake
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Desmond
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Phillip
authors.initials: P
authors.lastname: Sherman
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Quesada
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.|The Interdepartmental Program in Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D007150:Immunohistochemistry; D008253:Macaca mulatta; D062105:Molecular Docking Simulation; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000032:analysis*
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D000067759:Receptor for Advanced Glycation End Products
keywords: RAGE; fluorine-18; positron emission tomography; radiotracer