title: Targeting Metal-Aβ Aggregates with Bifunctional Radioligand [11C]L2-b and a Fluorine-18 Analogue [18F]FL2-b.
abstract: Interest in quantifying metal-Aβ speciesin vivoled to the synthesis and evaluation of [11C]L2-b and [18F]FL2-b as radiopharmaceuticals for studying the metallobiology of Alzheimer's disease (AD) using positron emission tomography (PET) imaging. [11C]L2-b was synthesized in 3.6% radiochemical yield (nondecay corrected,n= 3), >95% radiochemical purity, from the corresponding desmethyl precursor. [18F]FL2-b was synthesized in 1.0% radiochemical yield (nondecay corrected,n= 3), >99% radiochemical purity, from a 6-chloro pyridine precursor. Autoradiography experiments with AD positive and healthy control brain samples were used to determine the specificity of binding for the radioligands compared to [11C]PiB, a known imaging agent for β-amyloid (Aβ) aggregates. TheKdfor [11C]L2-b and [18F]FL2-b were found to be 3.5 and 9.4 nM, respectively, from those tissue studies. Displacement studies of [11C]L2-b and [18F]FL2-b with PiB and AV-45 determined that L2-b binds to Aβ aggregates differently from known radiopharmaceuticals. Finally, brain uptake of [11C]L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress (n= 2).
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The 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, 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: Maria V
authors.initials: MV
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: 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: 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: 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: 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: Geriatrics Research, Education, and Clinical Center, Veterans Affairs Ann Arbor Healthcare System , Ann Arbor, Michigan 48105, United States ; Department of Neurology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States ; Michigan Alzheimer Disease Center, The University of Michigan , Ann Arbor, Michigan 48105, 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 ; 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; amyloid-beta; carbon-11; fluorine-18; metal ions; metal-Aβ; positron emission tomography