Feasibility studies of radioiodinated pyridyl benzofuran derivatives as potential SPECT imaging agents for prion deposits in the brain

Takeshi Fuchigami; Masao Kawasaki; Hiroyuki Watanabe; Takehiro Nakagaki; Kodai Nishi; Kazunori Sano; Ryuichiro Atarashi; Mari Nakaie; Sakura Yoshida; Masahiro Ono; Noriyuki Nishida; Morio Nakayama

doi:10.1016/j.nucmedbio.2020.09.003

Feasibility studies of radioiodinated pyridyl benzofuran derivatives as potential SPECT imaging agents for prion deposits in the brain

Nucl Med Biol. 2020 Nov-Dec:90-91:41-48. doi: 10.1016/j.nucmedbio.2020.09.003. Epub 2020 Sep 15.

Authors

Affiliations

¹ 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.
² Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
³ Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
⁴ Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
⁵ Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
⁶ Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, 814-0180 Fukuoka, Japan.
⁷ Division of Microbiology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kiyotake-cho, Miyazaki 889-1692, Japan.
⁸ Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. Electronic address: nakmorio@gmail.com.

PMID: 32979726
DOI: 10.1016/j.nucmedbio.2020.09.003

Abstract

Introduction: Prion diseases are fatal neurodegenerative disorders caused by the deposition of abnormal prion protein aggregates (PrP^Sc) in the central nervous system. This study aimed to evaluate the use of iodinated pyridyl benzofuran (IPBF) derivatives as single-photon emission computed tomography (SPECT) probes for the detection of cerebral PrP^Sc deposits.

Methods: In vitro binding assays of IPBF derivatives were carried out in the recombinant mouse prion protein (rMoPrP) and brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice. SPECT imaging of 5-(5-[¹²³I]iodobenzofuran-2-yl)-N-methylpyridin-2-amine ([¹²³I]IPBF-NHMe) was performed on mBSE-infected and mock-infected mice.

Results: Fluorescence microscopy results showed that fluorescence signals of IPBF derivatives corresponded to the thioflavin-T positive amyloid deposits of PrP^Sc in the brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice. Among the IPBF derivatives, 5-(5-iodobenzofuran-2-yl)-N-methylpyridin-2-amine (IPBF-NHMe) exhibited the highest binding affinity to the recombinant mouse prion protein (rMoPrP) aggregates with a K_i of 14.3 nM. SPECT/computed tomography (CT) imaging and ex vivo autoradiography demonstrated that the [¹²³I]IPBF-NHMe distribution in brain tissues of mBSE-infected mice co-localized with PrP^Sc deposits.

Conclusion: [¹²³I]IPBF-NHMe appears to be a prospective SPECT tracer for monitoring prion deposits in living brain tissues.

Keywords: Amyloid; PrP(Sc); Prion diseases; Pyridyl benzofurans; Single photon emission computed tomography (SPECT).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzofurans / chemistry*
Brain / diagnostic imaging*
Brain / metabolism*
Feasibility Studies
Mice
Microscopy, Fluorescence
Prion Proteins / metabolism*
Pyridines / chemistry*
Tomography, Emission-Computed, Single-Photon / methods*

Substances

Benzofurans
Prion Proteins
Pyridines