Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT.
We report radioiodinated chalcone derivatives as new SPECT imaging probes for amyloid β (Aβ) plaques. The monoethyleneoxy derivative 2 and allyloxy derivative 8 showed a high affinity for Aβ(1-42) aggregates with Ki values of 24 and 4.5 nM, respectively. Fluorescent imaging demonstrated that 2 and 8 clearly stained thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In vitro autoradiography revealed that [(125)I]2 displayed no clear accumulation toward Aβ plaques in the brain sections of Tg2576 mice, whereas the accumulation pattern of [(125)I]8 matched with the presence of Aβ plaques both in the brain sections of Tg2576 mice and an AD patient. In biodistribution studies using normal mice, [(125)I]2 showed preferable in vivo pharmacokinetics (4.82%ID/g at 2 min and 0.45%ID/g at 60 min), while [(125)I]8 showed only a modest brain uptake (1.62%ID/g at 2 min) with slow clearance (0.56%ID/g at 60 min). [(125)I]8 showed prospective binding properties for Aβ plaques, although further structural modifications are needed to improve the blood brain barrier permeability and washout from brain.
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.
Takeshi
T
Fuchigami
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Yuki
Y
Yamashita
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Mamoru
M
Haratake
Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Masahiro
M
Ono
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Sakura
S
Yoshida
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Morio
M
Nakayama
D000544:Alzheimer Disease / Q000175:diagnosis; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005030:Ethylenes / Q000737:chemistry; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
C000593356:3-(4-(dimethylamino)phenyl)-1-(4-((3-iodoallyl)oxy)phenyl)prop-2-en-1-one; D016229:Amyloid beta-Peptides; D047188:Chalcones; D005030:Ethylenes; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C075222:amyloid beta-protein (1-42); D002599:Chalcone; C036216:ethylene
Alzheimer’s disease; Amyloid β plaque; Chalcone; Single photon emission computed tomography (SPECT)