Fluorinated Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains

Cheng, Yan; Ono, Masahiro; Kimura, Hiroyuki; Kagawa, Shingo; Nishii, Ryuichi; Kawashima, Hidekazu; Saji, Hideo

doi:10.1021/ml100082x

Cited by 38 publications

(36 citation statements)

References 28 publications

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“…IMPY and PIB were also screened using the same system for comparison. As shown in Table 1, all ligands with a dimethylamino group (30,31,33,42,43, and 45) displayed high binding affinity to Aβ 1−42 aggregates (K i < 10.0 nM). Similar to the findings reported previously, 30 the tertiary N,Ndimethylamino analogues were found to have higher affinities than their secondary N-methylamino analogues, especially for the pyridylbenzoxazole derivatives (e.g., 28 vs 30, 29 vs 31, 32 vs 33).…”

Section: ■ Results and Discussionmentioning

confidence: 94%

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Synthesis and Evaluation of Novel ¹⁸F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

Cui

Wang

et al. 2012

J. Med. Chem.

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A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for (18)F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [(18)F]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([(18)F]32) (K(i) = 8.0 ± 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [(18)F]32 to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [(18)F]32 is a promising Aβ imaging agent for PET and merits further evaluation in human subjects.

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Section: ■ Results and Discussionmentioning

confidence: 94%

“…Seven ligands with high affinity (29,31,32,33,41,43, and 44) were selected for 18 F labeling. In vitro autoradiography with sections of postmortem AD brain and Tg mouse brain confirmed the affinity of these tracers.…”

Section: ■ Conclusionmentioning

confidence: 99%

Synthesis and Evaluation of Novel ¹⁸F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

Cui

Wang

et al. 2012

J. Med. Chem.

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“…First, based on our previous research on radioiodinated and 11 C-labeled benzofuran derivatives (28, 29), we developed 4-(5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy) benzofuran-2-yl)-N,N-dimethylbenzenamine (FPHBF-1, Fig. 2), which has a fluoropolyethylene glycol side chain and a dimethylamino phenyl group (30). Although the penetration of brain tissues by this tracer was encouraging, the slow washout of this probe from the normal mouse brain made it unsuitable for imaging in vivo.…”

Section: Pet/spect Imaging Probes For Spsmentioning

confidence: 99%

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer’s Disease: Novel PET/SPECT Imaging Probes for Diagnosis of Alzheimer’s Disease

Ono

Saji

2012

J Pharmacol Sci

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Abstract. Alzheimer's disease (AD) is a neurodegenerative disease of the brain associated with irreversible cognitive decline, memory impairment, and behavioral changes. Postmortem brains of AD patients reveal neuropathologic features, in particular the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), which contain β-amyloid peptides and highly phosphorylated tau proteins. Currently, AD can only be definitively confirmed by postmortem histopathologic examination of SPs and NFTs in the brain. Therefore, SPs and NFTs in the brain may be useful as biomarkers for the differential diagnosis of AD; the detection of individual SPs and NFTs in vivo by positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) should improve diagnosis and also accelerate discovery of effective therapeutic agents for AD. Many PET/SPECT imaging probes for SPs have already been developed. Several of the PET probes have been shown in clinical trials to be useful for the imaging of β-amyloid plaques in living brain tissue. More recently, the development of PET/SPECT probes for in vivo imaging of NFTs is an active area of study in the field of molecular imaging because the appearance of NFT pathology correlates well with clinical severity of dementia. We will review current research on the development of PET/SPECT imaging probes for in vivo detection of SPs and NFTs and their application to diagnosis and therapy of AD.

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“…Thus we designed molecular probes for nuclear medicinal imaging the distribution of aggregates of Aβ and hyperphosphorylated tau protein in the brain of a patient with AD, which satisfied the following requirements: 1) high blood-brain barrier permeability; 2) high and specific binding ability to Aβ and tau aggregates; and 3) rapid elimination from normal regions of the brain. Consequently, we succeeded in developing 18 F-labeled pyridyl benzofuran derivative, 18 F-FPYBF-2, as a probe for PET imaging of Aβ plaques [28][29][30][31][32][33][34][35][36] and 123 I-labeled benzo imidazopyridine (BIP) derivative, BIP-3, as a probe for SPECT imaging of tau aggregates [37][38][39][40][41] (Fig. 3).…”

Section: Molecular Imaging Of β-Amyloid Plaques and Taumentioning

confidence: 99%

<i>In Vivo</i> Molecular Imaging

Saji

2017

Biological & Pharmaceutical Bulletin

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In vivo molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Among the methodologies used in in vivo molecular imaging, two methodologies are of great interest from the view of high sensitivity. One is nuclear medical imaging, and distribution and kinetics of a radiolabeled molecular probe are measured using positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The other is optical molecular imaging, and distribution and kinetics of a fluorescent probe are measured using a fluorescent imaging instrument. In this review, the development of imaging probes for these two methodologies is briefly discussed. In nuclear medical molecular imaging, based on structure-activity-biodistribution relationship studies for small molecule and the concept of "functional unit-binding multifunctional molecular probe" containing 3 functional units (target recognition unit, signal-releasing unit, linker unit) for peptides and proteins, we developed radiolabeled probes with high and specific accumulation to the target for neuroreceptors, β-amyloid plaques, and tau aggregates in the brain, tumors, atherosclerotic plaques, pancreatic β-cell, myocardial sympathetic nerves, and so on. We also discuss the progression of molecular imaging toward therapy (radiotheranotics). In in vivo optical molecular imaging, taking into account the characteristics of optical imaging, we designed tumor-specific optical imaging probes with characteristic imaging mechanism, including near-infrared (NIR) fluorescent probes and activatable probes. Furthermore, we developed a photoacoustic imaging probe, which enables highly sensitive and high-resolution imaging in deep tissues.

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Fluorinated Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains

Cited by 38 publications

References 28 publications

Synthesis and Evaluation of Novel ¹⁸F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

Synthesis and Evaluation of Novel ¹⁸F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer’s Disease: Novel PET/SPECT Imaging Probes for Diagnosis of Alzheimer’s Disease

<i>In Vivo</i> Molecular Imaging

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Fluorinated Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains

Cited by 38 publications

References 28 publications

Synthesis and Evaluation of Novel 18F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

Synthesis and Evaluation of Novel 18F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer’s Disease: Novel PET/SPECT Imaging Probes for Diagnosis of Alzheimer’s Disease

<i>In Vivo</i> Molecular Imaging

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Synthesis and Evaluation of Novel ¹⁸F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

Synthesis and Evaluation of Novel ¹⁸F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques