title: Evaluation of [(11)C]N-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary Tangles.
abstract: [(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [(11)C]MeI), 99% radiochemical purity, and 16095 Ci/mmol specific activity (n = 5). Log P was determined to be 2.18. A lack of brain uptake in rodent microPET imaging revealed [(11)C]NML to be a substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by pretreating with cyclosporin A to block the PGP. Contrastingly, [(11)C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [(11)C]NML uptake in the healthy primate brain of ∼1600 nCi/cc maximum at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiography between wild-type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [(11)C]NML in the cortex of brains expressing human tau. Further autoradiography with tau positive brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [(11)C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K d and Bmax values of [(11)C]NML as 700 pM and 0.214 fmol/μg, respectively.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Shao
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Carpenter
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The 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, The 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, The 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, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Fawaz
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The 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, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
authors.affiliation: Geriatrics Research, Education, and Clinical Center, VAAAHS , Ann Arbor, Michigan 48105, United States ; Department of Neurology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States ; Department of Neurology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Frey
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States ; The Interdepartmental Program in Medicinal Chemistry, The University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
keywords: Alzheimer's disease; carbon-11; neuroimaging; positron emission tomography imaging; tauopathies