title: Characterisation of radioiodinated flavonoid derivatives for SPECT imaging of cerebral prion deposits.
abstract: Prion diseases are fatal neurodegenerative diseases characterised by deposition of amyloid plaques containing abnormal prion protein aggregates (PrP(Sc)). This study aimed to evaluate the potential of radioiodinated flavonoid derivatives for single photon emission computed tomography (SPECT) imaging of PrP(Sc). In vitro binding assays using recombinant mouse PrP (rMoPrP) aggregates revealed that the 4-dimethylamino-substituted styrylchromone derivative (SC-NMe2) had higher in vitro binding affinity (Kd = 24.5 nM) and capacity (Bmax = 36.3 pmol/nmol protein) than three other flavonoid derivatives (flavone, chalcone, and aurone). Fluorescent imaging using brain sections from mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice demonstrated that SC-NMe2 clearly labelled PrP(Sc)-positive prion deposits in the mice brain. Two methoxy SC derivatives, SC-OMe and SC-(OMe)2, also showed high binding affinity for rMoPrP aggregates with Ki values of 20.8 and 26.6 nM, respectively. In vitro fluorescence and autoradiography experiments demonstrated high accumulation of [(125)I]SC-OMe and [(125)I]SC-(OMe)2 in prion deposit-rich regions of the mBSE-infected mouse brain. SPECT/computed tomography (CT) imaging and ex vivo autoradiography demonstrated that [(123)I]SC-OMe showed consistent brain distribution with the presence of PrP(Sc) deposits in the mBSE-infected mice brain. In conclusion, [(123)I]SC-OMe appears a promising SPECT radioligand for monitoring prion deposit levels in the living brain.
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fuchigami
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kawasaki
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ogawa
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.|Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Haratake
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Atarashi
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Nakagaki
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ubagai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Sakura
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002417:Cattle; D004195:Disease Models, Animal; D016643:Encephalopathy, Bovine Spongiform / Q000000981:diagnostic imaging / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000494:pharmacology; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D018620:PrPSc Proteins / Q000378:metabolism*; D011859:Radiography; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D005419:Flavonoids; D007457:Iodine Radioisotopes; D018620:PrPSc Proteins