Development of novel 123I-labeled pyridyl benzofuran derivatives for SPECT imaging of β-amyloid plaques in Alzheimer's disease.
Imaging of β-amyloid (Aβ) plaques in the brain may facilitate the diagnosis of cerebral β-amyloidosis, risk prediction of Alzheimer's disease (AD), and effectiveness of anti-amyloid therapies. The purpose of this study was to evaluate novel (123)I-labeled pyridyl benzofuran derivatives as SPECT probes for Aβ imaging. The formation of a pyridyl benzofuran backbone was accomplished by Suzuki coupling. [(123)I/(125)I]-labeled pyridyl benzofuran derivatives were readily prepared by an iododestannylation reaction. In vitro Aβ binding assays were carried out using Aβ(1-42) aggregates and postmortem human brain sections. Biodistribution experiments were conducted in normal mice at 2, 10, 30, and 60 min postinjection. Aβ labeling in vivo was evaluated by small-animal SPECT/CT in Tg2576 transgenic mice injected with [(123)I]8. Ex vivo autoradiography of the brain sections was performed after SPECT/CT. Iodinated pyridyl benzofuran derivatives showed excellent affinity for Aβ(1-42) aggregates (2.4 to 10.3 nM) and intensely labeled Aβ plaques in autoradiographs of postmortem AD brain sections. In biodistribution experiments using normal mice, all these derivatives displayed high initial uptake (4.03-5.49% ID/g at 10 min). [(125)I]8 displayed the quickest clearance from the brain (1.30% ID/g at 60 min). SPECT/CT with [(123)I]8 revealed higher uptake of radioactivity in the Tg2576 mouse brain than the wild-type mouse brain. Ex vivo autoradiography showed in vivo binding of [(123)I]8 to Aβ plaques in the Tg2576 mouse brain. These combined results warrant further investigation of [(123)I]8 as a SPECT imaging agent for visualizing Aβ plaques in the AD brain.
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Masahiro
M
Ono
Yan
Y
Cheng
Hiroyuki
H
Kimura
Hiroyuki
H
Watanabe
Kenji
K
Matsumura
Masashi
M
Yoshimura
Shimpei
S
Iikuni
Yoko
Y
Okamoto
Masafumi
M
Ihara
Ryosuke
R
Takahashi
Hideo
H
Saji
D000544:Alzheimer Disease / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000378:metabolism; D000818:Animals; D001572:Benzofurans; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008867:Microtomy; D010446:Peptide Fragments / Q000032:analysis* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics; D016707:Tissue Fixation; D015899:Tomography, Emission-Computed, Single-Photon
D016229:Amyloid beta-Peptides; D001572:Benzofurans; D003287:Contrast Media; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D011725:Pyridines; C075222:amyloid beta-protein (1-42)