Synthesis and Characterization of Hydroxyethylamino- and Pyridyl-Substituted 2-Vinyl Chromone Derivatives for Detection of Cerebral Abnormal Prion Protein Deposits

Mari Nakaie; Fumihiro Katayama; Takehiro Nakagaki; Masao Kawasaki; Sakura Yoshida; Akira Toriba; Kazuma Ogawa; Noriyuki Nishida; Morio Nakayama; Takeshi Fuchigami

doi:10.1248/cpb.c21-00902

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Synthesis and Characterization of Hydroxyethylamino- and Pyridyl-Substituted 2-Vinyl Chromone Derivatives for Detection of Cerebral Abnormal Prion Protein Deposits

Mari Nakaie, Fumihiro Katayama, Takehiro Nakagaki, Masao Kawasaki, Sakura Yoshida, Akira Toriba, Kazuma Ogawa, Noriyuki Nishida, Morio Nakayama, Takeshi Fuchigami

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Mari Nakaie
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
Fumihiro Katayama
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
Takehiro Nakagaki
Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University
Masao Kawasaki
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
Sakura Yoshida
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
Akira Toriba
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
Kazuma Ogawa
Laboratory of Clinical Analytical Sciences, Graduate School of Medical Sciences, Kanazawa University
Institute for Frontier Science Initiative, Kanazawa University
Noriyuki Nishida
Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University
Morio Nakayama
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
Takeshi Fuchigami Corresponding author
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University
Laboratory of Clinical Analytical Sciences, Graduate School of Medical Sciences, Kanazawa University

Keywords: prion disease, scrapie prion protein (PrP^Sc), 2-vinyl chromone, single-photon emission computed tomography (SPECT)

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2022 Volume 70 Issue 3 Pages 211-219

DOI https://doi.org/10.1248/cpb.c21-00902

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Abstract

Prion diseases are fatal neurodegenerative diseases characterized by the deposition of abnormal prion protein aggregates (PrP^Sc) in the brain. In this study, we developed hydroxyethylamino-substituted styrylchromone (SC) and 2-(2-(pyridin-3-yl)vinyl)-4H-chromen-4-one (VPC) derivatives for single-photon emission computed tomography (SPECT) imaging of PrP^Sc deposits in the brain. The binding affinity of these compounds was evaluated using recombinant mouse prion protein (rMoPrP) aggregates, which resulted in the inhibition constant (K_i) value of 61.5 and 88.0 nM for hydroxyethyl derivative, (E)-2-(4-((2-hydroxyethyl)amino)styryl)-6-iodo-4H-chromen-4-one (SC-NHEtOH) and (E)-2-(4-((2-hydroxyethyl)(methyl)amino)styryl)-6-iodo-4H-chromen-4-one (SC-NMeEtOH), respectively. However, none of the VPC derivatives showed binding affinity for the rMoPrP aggregates. Fluorescent imaging demonstrated that the accumulation pattern of SC-NHEtOH matched with the presence of PrP^Sc in the brain slices from mouse-adapted bovine spongiform encephalopathy-infected mice. A biodistribution study of normal mice indicated low initial brain uptake of [¹²⁵I]SC-NHEtOH (0.88% injected dose/g (% ID/g) at 2 min) despite favorable washout from the brain (0.26% ID/g, at 180 min) was displayed. [¹²⁵I]SC-NHEtOH exhibited binding affinities to both artificial prion aggregates as well as prion deposits in the brain. However, significant improvement in the binding affinity for PrP^Sc and blood–brain barrier permeability is necessary for the development of successful in vivo imaging probes for the detection of cerebral PrP^Sc in the brain.

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