Synthesis and biological evaluation of novel styryl benzimidazole derivatives as probes for imaging of neurofibrillary tangles in Alzheimer's disease

Kenji Matsumura; Masahiro Ono; Masashi Yoshimura; Hiroyuki Kimura; Hiroyuki Watanabe; Yoko Okamoto; Masafumi Ihara; Ryosuke Takahashi; Hideo Saji

doi:10.1016/j.bmc.2013.02.054

Synthesis and biological evaluation of novel styryl benzimidazole derivatives as probes for imaging of neurofibrillary tangles in Alzheimer's disease

Bioorg Med Chem. 2013 Jun 1;21(11):3356-62. doi: 10.1016/j.bmc.2013.02.054. Epub 2013 Mar 29.

Authors

Kenji Matsumura¹, Masahiro Ono, Masashi Yoshimura, Hiroyuki Kimura, Hiroyuki Watanabe, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hideo Saji

Affiliation

¹ Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.

PMID: 23601814
DOI: 10.1016/j.bmc.2013.02.054

Abstract

This paper describes the synthesis and biological evaluation of styrylbenzimidazole (SBIM) derivatives as agents for imaging neurofibrillary tangles (NFT) in patients with Alzheimer's disease (AD). SBIM derivatives were prepared with 4-iodobenzene-1,2-diamine and substituted cinnamaldehydes. In binding experiments using recombinant tau and Aβ(1-42) aggregates, SBIM-3 showed higher affinity for the tau aggregates than Aβ(1-42) aggregates (ratio of K(d) values was 2.73). In in vitro autoradiography and fluorescent staining, [(125)I]SBIM-3 (or SBIM-3) bound NFT in sections of AD brain tissue. In biodistribution experiments using normal mice, all [(125)I]SBIM derivatives showed high initial uptake into (3.20-4.11%ID/g at 2 min after the injection) and rapid clearance from (0.12-0.33%ID/g at 60 min after the injection) the brain. In conclusion, appropriate structural modifications of SBIM derivatives could lead to more useful agents for the in vivo imaging of NFT in AD brains.

Publication types

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

MeSH terms

Acrolein / analogs & derivatives
Acrolein / chemistry
Aged
Aged, 80 and over
Alzheimer Disease / diagnostic imaging
Alzheimer Disease / pathology
Amyloid beta-Peptides / chemistry*
Amyloid beta-Peptides / ultrastructure
Animals
Autoradiography
Benzimidazoles / chemical synthesis*
Benzimidazoles / pharmacokinetics
Brain / diagnostic imaging*
Brain / pathology
Brain / ultrastructure
Female
Humans
Iodine Radioisotopes
Iodobenzenes / chemistry
Male
Mice
Neurofibrillary Tangles / diagnostic imaging*
Neurofibrillary Tangles / pathology
Neurofibrillary Tangles / ultrastructure
Peptide Fragments / chemistry*
Peptide Fragments / ultrastructure
Positron-Emission Tomography
Radiopharmaceuticals / chemical synthesis*
Radiopharmaceuticals / pharmacokinetics
Tissue Distribution
tau Proteins / chemistry*
tau Proteins / ultrastructure

Substances

Amyloid beta-Peptides
Benzimidazoles
Iodine Radioisotopes
Iodobenzenes
Peptide Fragments
Radiopharmaceuticals
amyloid beta-protein (1-42)
tau Proteins
Acrolein
cinnamaldehyde