Radioiodinated Flavones for in Vivo Imaging of β-Amyloid Plaques in the Brain

Ono, Masahiro; Yoshida, Naoko; Ishibashi, Keiichiro; Haratake, Mamoru; Arano, Yasushi; Mori, Hiroshi; Nakayama, Morio

doi:10.1021/jm050635e

Cited by 73 publications

(64 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

“…The chelation ligand (BAT) were synthesized according to methods reported previously with some slight modifications (26). The most useful method of preparing flavones is known as the Baker-Venkataraman transformation 23 . A hydroxyacetophenone was first converted into a benzoyl ester (1) which was then treated with a base, forming a 1,3-diketone (2).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Ono Et Al 3/38mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have previously reported Aβ imaging agents based on flavonoid derivatives, such as flavones 15,16 , chalcones [17][18][19][20] , aurones 21,22 , and styrylchromones 23 studies demonstrated that chalcone derivatives fluoro-pegylated at the p-position of the 1-phenyl ring showed a sufficient brain uptake with a good binding capacity to Aβ plaques 19 . In addition, radioiodinated flavonoids, such as flavone and aurone derivatives, with a methoxy or oligoethyleneoxy group at the p-position of the 3-phenyl ring have the properties of high brain uptake and rapid clearance from the brain without significant decrease in the binding affinity for Aβ 15,22 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

Fuchigami¹,

Yamashita²,

Haratake³

et al. 2014

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Modifications of the benzamide moiety of the general structure 1 aimed at lowering the lipophilicity might allow for penetrating the brain while maintaining favorable Aβ-plaque binding characteristics. Recent studies with modified amyloid ligands [11][12][13] provide encouragement to further explore this route. …”

mentioning

confidence: 99%

Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque

Hausner

Alagille

Koren

et al. 2009

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

A series of novel 5-and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer's Disease (AD) related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Aβ1-40 peptide of several of these compounds were in the low-nanomolar range. The lowest K i of 9.3 nM was found for N-(2-(4-(dimethylamino)phenyl)-1,3-benzoxazol-5-yl)-4-iodobenzamide (1e). Its 123 I-radiolabeled form ([ 123 I]1e) was subsequently prepared by iododestannylation of the corresponding tributylstannyl precursor and evaluated in vivo in a baboon model using SPECT imaging. Contrary to our expectations, 1e did not cross the blood-brain-barrier (BBB) to any significant extent.Alzheimer's Disease (AD) is the most common form of dementia in people aged 65 and older. Currently, several million patients suffer from AD in the US alone, and with the aging of the baby-boom generation, this number is expected to increase. AD is a neurodegenerative disease that gradually leads to severe memory loss. Abundant insoluble neurotoxic deposits of Aβ1-40 and Aβ1-42 peptides on neurons ("Aβ-plaque" or "amyloid plaque"), resulting from cleavage of the amyloid precursor protein (APP) by specific proteases, are one of the characteristic pathological changes occurring in AD. Currently, a definite confirmation of AD is attained only by post-mortem histopathology of the brain. The ability to image amyloid plaque noninvasively in vivo would allow for early diagnosis of AD and evaluation of medication treatment progress in AD patients. Recently, it was reported that non-ionic analogues of Thioflavin T, an ionic imaging dye, penetrate the blood-brain barrier (BBB) and show high affinity for Aβ-plaque. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. We reasoned that replacing the original iodo substituent with an amine functionality would allow for easy attachment of different groups via an amide bond. Here we report the synthesis and in vitro and in vivo evaluation of 5-and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles (1) as potential imaging agents for amyloid plaque. NIH Public AccessCompounds of the general structure 1 were synthesized according to Scheme 1. The 1,3-benzoxazole nucleus was formed via a boronic-acid-catalyzed condensation of the corresponding aminonitrophenols with 4-(dimethylamino)benzoic acid. Reduction of the nitro group to amino followed by condensation with the appropriate aromatic acid chloride gave the intended structures. Purity of the target compounds was confirmed by 1 H-and 13 C-NMR, hig...

show abstract

Radioiodinated Flavones for in Vivo Imaging of β-Amyloid Plaques in the Brain

Cited by 73 publications

References 28 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

Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque

Contact Info

Product

Resources

About