title: Synthesis and evaluation of 6-(3-[(18)F]fluoro-2-hydroxypropyl)-substituted 2-pyridylbenzothiophenes and 2-pyridylbenzothiazoles as potential PET tracers for imaging Aβ plaques.
abstract: 3-[(18)F]Fluoro-2-hydroxypropyl substituted compounds were synthesized and evaluated as novel (18)F-labeled PET tracers for imaging Aβ plaque in a living brain. All compounds exhibited high binding affinities toward the synthetic Aβ1-42 aggregate and/or Alzheimer's disease brain homogenate. In the microPET study with normal mice, the 3-[(18)F]fluoro-2-hydroxypropyl substituted compounds resulted in fast brain washout by reducing the lipophilicities of the compounds. Intriguingly, (S)-configured PET tracers, (S)-[(18)F]1b and (S)-[(18)F]1c, exhibited a 2.8 and 4.0-fold faster brain washout rate at a peak/30 min in the mouse brain than the corresponding (R)-configured PET tracers despite there being no meaningful difference in binding affinities toward Aβ plaque. A further evaluation of (S)-[(18)F]1c with healthy rhesus monkeys also revealed excellent clearance from the frontal cortex with ratios of 7.0, 16.0, 30.0 and 49.0 at a peak/30, 60, 90, and 120 min, respectively. These results suggest that (S)-[(18)F]1c may be a potential PET tracer for imaging Aβ plaque in a living brain.
authors.affiliation: Research Institute of Labeling, FutureChem Co., Ltd, Seoul 04782, Republic of Korea.
authors.forename: Byoung Se
authors.initials: BS
authors.lastname: Lee
authors.affiliation: Research Institute of Labeling, FutureChem Co., Ltd, Seoul 04782, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Chu
authors.affiliation: Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Kwon
authors.affiliation: Research Institute of Labeling, FutureChem Co., Ltd, Seoul 04782, Republic of Korea.
authors.forename: Chansoo
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
authors.forename: Uthaiwan
authors.initials: U
authors.lastname: Sirion
authors.affiliation: Global Drug Discovery-Molecular Imaging, Bayer Healthcare AG, 13353 Berlin, Germany.
authors.forename: Damian
authors.initials: D
authors.lastname: Brockschnieder
authors.affiliation: Global Drug Discovery-Molecular Imaging, Bayer Healthcare AG, 13353 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dyrks
authors.affiliation: Department of Nuclear Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Department of Nuclear Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Research Institute of Labeling, FutureChem Co., Ltd, Seoul 04782, Republic of Korea; Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea. Electronic address: dychi@sogang.ac.kr.
authors.forename: Dae Yoon
authors.initials: DY
authors.lastname: Chi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D051379:Mice; D049268:Positron-Emission Tomography; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D013844:Thiazoles; D013876:Thiophenes
keywords: Alzheimer’s disease (AD); Positron Emission Tomography (PET); β-Amyloid (Aβ)