18F-labeled flavones for in vivo imaging of β-amyloid plaques in Alzheimer’s brains

Ono, Masahiro; Watanabe, Rumi; Kawashima, Hidekazu; Kawai, Tomoki; Watanabe, Hiroyuki; Haratake, Mamoru; Saji, Hideo; Nakayama, Morio

doi:10.1016/j.bmc.2009.01.025

Cited by 35 publications

(35 citation statements)

References 20 publications

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“…Recently, we have reported that flavonoids including chalcone, flavone, and aurone serve as useful molecular scaffolds in the development of imaging agents for β-amyloid plaques in the brain [23][24][25][26][27][28] . Initially, we designed and synthesized four 99m Tc-labeled In the present study, to develop more useful 99m Tc imaging agents for the clinical diagnosis of AD, we synthesized two flavone and aurone derivatives with BAT as a chelation ligand.…”

Section: Ono Et Al 3/38mentioning

confidence: 99%

“…Based on this success, efforts were made to search for comparable 99m Tc imaging agents that target binding sites on -amyloid plaques in the brain of AD patients. Several 99m Tc-labeled imaging probes have been developed (Figure 1), but no clinical study of them has been reported [19][20][21][22] .Recently, we have reported that flavonoids including chalcone, flavone, and aurone serve as useful molecular scaffolds in the development of imaging agents for β-amyloid plaques in the brain [23][24][25][26][27][28] . Initially, we designed and synthesized four 99m Tc-labeled In the present study, to develop more useful 99m Tc imaging agents for the clinical diagnosis of AD, we synthesized two flavone and aurone derivatives with BAT as a chelation ligand.…”

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confidence: 99%

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99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

Ono

Ikeoka

Watanabe

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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Two 99m Tc/Re complexes based on flavone and aurone were tested as potential probes for imaging -amyloid plaques using single photon emission computed tomography. Both 99m Tc-labeled derivatives showed higher affinity for A aggregates than did 99m Tc-BAT. In sections of brain tissue from an animal model of AD, the Re-flavone derivative 9 and Re-aurone derivative 19 intensely stained -amyloid plaques. In biodistribution experiments using normal mice, 99m Tc-labeled flavone and aurone displayed similar radioactivity pharmacokinetics. With additional modifications to improve their brain uptake, 99m Tc complexes based on the flavone or aurone scaffold may serve as probes for imaging cerebral -amyloid plaques Key words: Alzheimer's disease, -amyloid plaque, Tc-99m, single photon emission computed tomography (SPECT), imaging. Ono et al. 3/38Alzheimer's disease (AD) is a neurodegenerative disorder of the brain associated with irreversible cognititive decline, memory impairment, and behavioral changes.Currently, the only definitive confirmation of AD is by postmortem histopathological examination of -amyloid plaques in the brain. The early appraisal of clinical symptoms for a diagnosis of AD is often difficult and unreliable. Numerous reports suggest the accelerated accumulation of -amyloid plaques in the brain to be a key risk factor associated with AD. Consequently, the detection of individual -amyloid plaques in vivo by single photon emission tomography (SPECT) or positron emission tomography (PET) should improve the diagnosis of and also accelerate the discovery of effective therapeutic agents for AD [1][2][3][4] There are more SPECT scanners than PET imaging devices installed for routine clinical imaging, which provides a certain advantage to using SPECT imaging agents. Since SPECT is more valuable than PET in terms of routine diagnostic use, the development of more useful Aβ imaging agents for SPECT has been a critical issue. Although many radioiodinated SPECT imaging agents for detecting β-amyloid plaques have been reported, there are few reports on the development of 99m Tc imaging agents. Ono et al. 4/38 99m Tc (T 1/2 = 6.01 h, 141 keV) has become the most commonly used radionuclide in diagnostic nuclear medicine for several reasons: it is readily produced by an 99 Mo/ 99m Tc generator, the gamma-ray energy it emits is suitable for detection, and its physical half-life is compatible with the biological localization and residence time required for imaging. Its ready availability, essentially 24 h a day, and easiness of use make it the radionuclide of choice. New 99m Tc-labeled imaging agents will provide simple, convenient, and widespread SPECT-based imaging methods for detecting and eventually quantifying-amyloid plaques in living brain tissue.It has been reported that a dopamine transporter imaging agent, [ 99m Tc]TRODAT-1, is useful to detect the loss of dopamine neurons in the basal ganglia associated with Parkinson's disease. This is the first example of a 99m Tc imaging agent t...

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Section: Ono Et Al 3/38mentioning

confidence: 99%

mentioning

confidence: 99%

99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

Ono

Ikeoka

Watanabe

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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“…1), although clinically available compounds have not yet been developed. [13][14][15][16][17][18][19][20][21][22] We found that radioiodinated styrylchromones (SCs) with amino groups (NH 2 , NHMe, and NMe 2 ) bind to Ab aggregates with high binding affinities. However, their initial uptake and washout from normal mice brain tissue were inadequate for in vivo imaging.…”

Section: Introductionmentioning

confidence: 98%

Development of alkoxy styrylchromone derivatives for imaging of cerebral amyloid-β plaques with SPECT

Fuchigami

Ogawa

Yamashita

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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We report here the development of radioiodinated styrylchromone derivatives with alkoxy groups as single photon emission computed tomography (SPECT) imaging probes for cerebral amyloid-β (Aβ) plaques. Among the derivatives, the methoxy derivative 14 and the dimethoxy derivative 15 displayed relatively high affinity for the Aβ(1-42) aggregates with K(i) values of 22 and 46 nM, respectively. Fluorescent imaging demonstrated that 14 and 15 clearly labeled thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In the in vivo studies, [(125)I]14 and [(125)I]15 showed high initial brain uptake expressed as the percentage of the injected dose per gram (2.25% and 2.49% ID/g at 2 min, respectively) with favorable clearance (0.12% and 0.20% ID/g at 180 min, respectively) from the brain tissue of normal mice. Furthermore, in vitro autoradiography confirmed that [(125)I]15 binds thioflavin-S positive regions in Tg2576 mouse brain sections. The derivative 15 may be a potential scaffold for the development of in vivo imaging probes targeting Aβ plaques in the brain. In particular, further structural modifications are required to improve the compounds binding affinity for Aβ.

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“…Therefore, in vivo non-invasive imaging of ␤-amyloid plaques in the living brain would be necessary for early detection of AD [5,6], and many radio-labeled biomarkers for direct mapping ␤-amyloid plaques by SPECT and PET have been reported [7][8][9][10][11][12][13][14][15]. Currently, radio-iodinated and radio-fluorided flavone derivatives have been undertaken to develop novel probes for targeting A␤ plaques by Ono et al [16,17], the corresponding biological evaluation (radioautography and biodistribution) results, in addition of the hypotoxicity of the flavone derivatives, suggested that efforts should focused on the development of diagnostic flavone derivatives labeled by isotopes of 99m Tc, 123 I, 18 F, or 11 C as candidates for the plaques imaging. However, it takes on a lot of sophisticated experiments to obtain the final and ideal radio-tracers usually, thus in order to select several flavones rapidly and efficiently for radiolabelling and biological evaluation, we sought to elucidate the relationship between the concentrations of the ligands and fluorescence intensities by in vitro measuring the K d s that could be used to evaluate the binding affinities when these flavones binding with A␤ aggregates protein, which was often used as an in vitro model of the ␤-amyloid plaques.…”

Section: Introductionmentioning

confidence: 99%

Binding research on flavones as ligands of β-amyloid aggregates by fluorescence and their 3D-QSAR, docking studies

Yang

Zhu

Chen

et al. 2010

Journal of Molecular Graphics and Modelling

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18F-labeled flavones for in vivo imaging of β-amyloid plaques in Alzheimer’s brains

Cited by 35 publications

References 20 publications

99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

Development of alkoxy styrylchromone derivatives for imaging of cerebral amyloid-β plaques with SPECT

Binding research on flavones as ligands of β-amyloid aggregates by fluorescence and their 3D-QSAR, docking studies

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