title: Development of radioiodinated acridine derivatives for in vivo imaging of prion deposits in the brain.
abstract: Prion diseases are caused by deposition of abnormal prion protein aggregates (PrPSc) in the central nervous system. This study aimed to develop in vivo imaging probes that can detect cerebral PrPScdeposits. We synthesized several quinacrine-based acridine (AC) derivatives with 2,9-substitution and radioiodinated them. The AC derivatives were evaluated as prion-imaging probes using recombinant mouse prion protein (rMoPrP) aggregates and brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice. The distribution of these compounds in mice was also evaluated. The 2-methoxy derivative [125I]2 exhibited the highest binding affinity for rMoPrP aggregates with an equilibrium dissociation constant (Kd) value of 43.4nM. Fluorescence imaging with 2 showed clear signals at the thioflavin T (ThT)-positive amyloid deposits in the mBSE-infected mouse brain. Although a discrepancy was observed between the in vitro binding of AC derivatives to the aggregates and in vivo distribution of these compounds in the brain and we failed to identify prospective prion-imaging probes in this study, the AC derivatives may be considered a useful scaffold for the development of in vivo imaging probes. Further chemical modification of these AC derivatives may discover clinically applicable prion imaging probes.
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. Electronic address: t-fuchi@nagasaki-u.ac.jp.
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: Nobuya
authors.initials: N
authors.lastname: Kobashi
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 Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Atarashi
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: 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: 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. Electronic address: morio@nagasaki-u.ac.jp.
authors.forename: Morio
authors.initials: M
authors.lastname: Nakayama
mesh_terms: D000166:Acridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D061605:Administration, Intravenous; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D057054:Molecular Imaging; D015394:Molecular Structure; D017096:Prion Diseases / Q000000981:diagnostic imaging*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000166:Acridines; D007457:Iodine Radioisotopes
keywords: Acridine; PrP(Sc); Prion disease; Quinacrine; Single photon emission computed tomography (SPECT)