title: High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.
abstract: Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Fawaz
authors.forename: Allen F
authors.initials: AF
authors.lastname: Brooks
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Rodnick
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Carpenter
authors.forename: Xia
authors.initials: X
authors.lastname: Shao
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Desmond
authors.forename: Phillip
authors.initials: P
authors.lastname: Sherman
authors.forename: Carole A
authors.initials: CA
authors.lastname: Quesada
authors.forename: Brian G
authors.initials: BG
authors.lastname: Hockley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Frey
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D064747:Lansoprazole / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011323:Primates; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013494:Supranuclear Palsy, Progressive / Q000000981:diagnostic imaging* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; C054369:MAPT protein, human; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D064747:Lansoprazole