Shozo Furumoto

Tohoku University, Sendai, Kagoshima, Japan

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Publications (82)181.51 Total impact

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    ABSTRACT: One approach to creating more beneficial therapeutic antibodies is to develop bispecific antibodies (bsAbs), particularly IgG-like formats with tetravalency, which may provide several advantages such as multivalent binding to each target antigen. Although the effects of configuration and antibody-fragment type on the function of IgG-like bsAbs have been studied, there have been only a few detailed studies of the influence of the variable fragment domain order. Here, we prepared four types of hEx3-scDb-Fc, IgG-like bsAbs, built from a single-chain hEx3-Db (humanized bispecific diabody [bsDb] that targets epidermal growth factor receptor and CD3), to investigate the influence of domain order and fusion manner on the function of a bsDb with an Fc fusion format. Higher cytotoxicities were observed with hEx3-scDb-Fcs with a variable light domain (VL)-variable heavy domain (VH) order (hEx3-scDb-Fc-LHs) compared with a VH-VL order, indicating that differences in the Fc fusion manner do not affect bsDb activity. In addition, flow cytometry suggested that the higher cytotoxicities of hEx3-scDb-Fc-LH may be attributable to structural superiority in cross-linking. Interestingly, enhanced degradation resistance and prolonged in vivo half-life were also observed with hEx3-scDb-Fc-LH. hEx3-scDb-Fc-LH and its IgG2 variant exhibited intense in vivo antitumor effects, suggesting that Fc-mediated effector functions are dispensable for effective anti-tumor activities, which may cause fewer side effects. Our results show that merely rearranging the domain order of IgG-like bsAbs can enhance not only their antitumor activity, but also their degradation resistance and in vivo half-life, and that hEx3-scDb-Fc-LHs are potent candidates for next-generation therapeutic antibodies.
    mAbs 07/2014; 6(5). · 5.28 Impact Factor
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    ABSTRACT: Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer's disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer (18)F-THK5105 in 16 human subjects including eight patients with Alzheimer's disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both (18)F-THK5105 and (11)C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for (18)F-THK5105 and (11)C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher (18)F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent (18)F-THK5105 retention. Compared with high frequency (100%) of (18)F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal (18)F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's disease. In contrast, (11)C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with (18)F-THK5105 retention in the neocortex. In healthy control subjects, (18)F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike (11)C-Pittsburgh compound B, (18)F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, (18)F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimer's disease.
    Brain 03/2014; · 9.92 Impact Factor
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    ABSTRACT: The introduction of tau imaging agents such as 18F-THK523, offers new hope for the in vivo assessment of tau deposition in tauopathies such as Alzheimer's disease (AD), where preliminary 18F-THK523-PET studies demonstrated significantly higher cortical retention of 18F-THK523 in AD compared to age-matched healthy individuals. In addition to AD, tau imaging with PET may also be of value to assess non-AD tauopathies, such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease (PiD). To further investigate the ability of THK523 to recognize tau lesions, we undertook immunohistochemical and fluorescent studies in serial brain sections from AD (n = 3), CBD (n = 2), PSP (n = 1), PiD (n = 2) and Parkinson's disease (PD, n = 2). In addition to the neuropathological analysis, one PSP patient had undergone a 18F-THK523 PET scan five months before death. While THK523 labeled tau-containing lesions such as neurofibrillary tangles and neuropil threads in the hippocampus and frontal regions of AD brains, it failed to label tau-containing lesions in non-AD tauopathies. Furthermore, while THK523 faintly labeled dense cored amyloid-beta plaques in the AD frontal cortex, it failed to label alpha-synuclein containing Lewy bodies in PD brain sections. This study suggests that 18F-THK523 selectively binds to paired helical filament-tau in AD brains but does not bind to tau lesions in non-AD tauopathies, nor to alpha-synuclein in PD brains.
    Alzheimer's Research and Therapy 02/2014; 6(1):11. · 4.39 Impact Factor
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    ABSTRACT: Diagnosis of tauopathies such as Alzheimer's disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate (18)F-THK523 as a potential tau imaging tracer. Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as (18)F-THK523 and (11)C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for (18)F-THK523 and (11)C-PIB were estimated for all participants. Correlational analyses were performed between global and regional (18)F-THK523, (11)C-PIB, cognition and brain volumetrics. (18)F-THK523 presented with fast reversible kinetics. Significantly higher (18)F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical (18)F-THK523 retention did not correlate with Aβ distribution as assessed by (11)C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike (11)C-PIB, hippocampal (18)F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy. (18)F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical (18)F-THK523 retention in AD patients as well as the association of hippocampal (18)F-THK523 retention with cognitive parameters and hippocampal volume suggests (18)F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high (18)F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.
    European Journal of Nuclear Medicine 02/2014; · 4.53 Impact Factor
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    ABSTRACT: To examine the usefulness of the early phase [(11)C]BF-227 positron emission tomography (PET) for (1) conferring additional diagnostic value by providing perfusion-like information and (2) obtaining the appropriate anatomical standardization (AS) using three-dimensional stereotactic surface projection (3D-SSP) method. This study included 20 mild cognitive impairment (MCI), 19 Alzheimer's disease (AD), and 17 normal cognitive (NC) subjects. Early- and late-phase BF-227 PET images were obtained 0-10 and 40-60 min after the injection, respectively. AS for late-phase BF-227 images were performed by 2 methods: (1) method A, for AS of late-phase BF-227 images using (8)F-fluorodeoxyglucose (FDG) images of the same subject and (2) method B, for AS of late-phase BF-227 images using early phase BF-227 images. Method B was successfully used for AS in all cases. The Z score maps of 3D-SSP analyses of FDG PET and early phase BF-227 PET for AD and MCI groups showed a typical AD-like pattern. Regional analyses revealed that the early phase BF-227 PET showed significant differences between AD and NC, and MCI and NC. The early phase BF-227 PET images showed significant abnormal findings for the AD and MCI groups. AS of late-phase BF-227 images using early phase BF-227 images were successful, and enabled appropriate 3D-SSP analyses.
    Japanese journal of radiology 01/2014; · 0.73 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia. Senile plaques, consisting of β-amyloid, and neurofibrillary tangles (NFTs), composed of tau protein, are representative pathological hallmarks of AD. It is believed that the accumulation of NFTs precedes the onset of clinical symptoms of AD and correlates with the progression of memory dysfunction. Thus, the use of noninvasive detection techniques including radiolabeled probes and positron emission tomography (PET) will facilitate early diagnosis or staging of AD. In this study, we synthesized and evaluated novel hydroxylated 2-arylquinoline derivatives as tau imaging PET probes. The binding affinities of compounds for tau were evaluated by fluorescent staining of the AD hippocampal section and a competitive binding assay using [(18) F]THK-523. THK-951 showed high binding affinity for tau pathology in an AD brain section and K18Δ280K fibrils (Ki = 20.7 nM); thus, we radiosynthesized a (11) C-labeled THK-951 and further studied its potential as a tau PET probe. The [(11) C]THK-951 demonstrated excellent kinetics in a normal mouse brain (3.23% ID/g at 2 min postinjection and 0.15% ID/g at 30 min postinjection) and showed the labeling of NFTs in an AD brain section by autoradiography assay. These findings indicate the availability of [(11) C]THK-951 for in vivo PET imaging of tau pathology in AD. Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 01/2014; 57(1):18-24.
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    ABSTRACT: Accumulation of intracellular tau fibrils has been the focus of research on the mechanisms of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we have developed a class of tau ligands, phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs), for visualizing diverse tau inclusions in brains of living patients with AD or non-AD tauopathies and animal models of these disorders. In vivo optical and positron emission tomographic (PET) imaging of a transgenic mouse model demonstrated sensitive detection of tau inclusions by PBBs. A pyridinated PBB, [(11)C]PBB3, was next applied in a clinical PET study, and its robust signal in the AD hippocampus wherein tau pathology is enriched contrasted strikingly with that of a senile plaque radioligand, [(11)C]Pittsburgh Compound-B ([(11)C]PIB). [(11)C]PBB3-PET data were also consistent with the spreading of tau pathology with AD progression. Furthermore, increased [(11)C]PBB3 signals were found in a corticobasal syndrome patient negative for [(11)C]PIB-PET.
    Neuron 09/2013; 79(6):1094-108. · 15.77 Impact Factor
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    ABSTRACT: The construction of antibody fragments has the potential to reduce the high cost of therapeutic antibody production, but the structures of these fragments, with monovalency and the lack of an Fc region, can lead to reduced function. Multimerization is one strategy for recovering function that also yields better tumor-to-blood ratios than IgGs or monomeric antibody fragments because of rapid tumor uptake and clearance. Here, we constructed single-chain variable fragment (scFv) multimers by modifying the linker length and domain order of the humanized anti-EGFR antibody 528 (h528) and tested their ability to inhibit tumor growth. The h528 scFv multimers, expressed using a bacterial expression system, were successfully fractionated and inhibited cancer growth in a multimerization-dependent manner, whereas the h528 scFv monomer showed no inhibition. h528 scFv trimers with the VH-VL domain order and no linkers showed the highest in vitro and in vivo anti-tumor effects, which were comparable to those of the approved anti-EGFR therapeutic antibodies Cetuximab and Panitumumab. The trimers were also structurally stable in vitro and in vivo, which may be attributable to a strong interaction between the VH and VL of h528 Fv. Thus, h528 scFv multimers, especially trimers, are attractive as the next generation of anti-EGFR therapeutic antibodies and offer the possibility of low cost production. This article is protected by copyright. All rights reserved.
    FEBS Journal 07/2013; · 4.25 Impact Factor
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    ABSTRACT: Selective visualization of amyloid-β and tau protein deposits will help to understand the pathophysiology of Alzheimer's disease (AD). Here, we introduce a novel fluorescent probe that can distinguish between these two deposits by multispectral fluorescence imaging technique. Fluorescence spectral analysis was performed using AD brain sections stained with novel fluorescence compounds. Competitive binding assay using [(3)H]-PiB was performed to evaluate the binding affinity of BF-188 for synthetic amyloid-β (Aβ) and tau fibrils. In AD brain sections, BF-188 clearly stained Aβ and tau protein deposits with different fluorescence spectra. In vitro binding assays indicated that BF-188 bound to both amyloid-β and tau fibrils with high affinity (K i < 10 nM). In addition, BF-188 showed an excellent blood-brain barrier permeability in mice. Multispectral imaging with BF-188 could potentially be used for selective in vivo imaging of tau deposits as well as amyloid-β in the brain.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 07/2013; · 2.47 Impact Factor
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    ABSTRACT: Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers. (18)F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice. In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-μM concentrations. (18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.
    Journal of Nuclear Medicine 07/2013; · 5.77 Impact Factor
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    ABSTRACT: 2-Deoxy-2-(18)F-fluoro-d-mannose ((18)F-FDM) is an (18)F-labeled mannose derivative and a stereoisomer of (18)F-FDG. Our preliminary study demonstrated that (18)F-FDM accumulated in tumors to the same extent as (18)F-FDG, with less uptake in the brain and faster clearance from the blood. However, detailed studies on the uptake of (18)F-FDM in tumors have not been conducted. We undertook this study to establish a practical method of (18)F-FDM synthesis based on an (18)F-nucleophilic substitution (SN2) reaction and to advance the biologic characterization of (18)F-FDM for potential application as a tumor-imaging agent. We synthesized 4,6-O-benzylidene-3-O-ethoxymethyl-1-O-methyl-2-O-trifluoromethanesulfonyl-β-d-glucopyranoside as a precursor for the nucleophilic synthesis of (18)F-FDM. The precursor was radiofluorinated with (18)F-KF/Kryptofix222, followed by removal of the protecting groups with an acid. (18)F-FDM was purified by preparative high-performance liquid chromatography and then subjected to in vitro evaluation regarding phosphorylation by hexokinase as well as uptake and metabolism in AH109A tumor cells. The in vivo properties of (18)F-FDM were examined in Donryu rats bearing AH109A tumor cells by biodistribution studies and imaging with a small-animal PET system. We radiosynthesized (18)F-FDM in sufficient radiochemical yields (50%-68%) with excellent purities (97.6%-98.7%). (18)F-FDM was phosphorylated rapidly by hexokinase, resulting in 98% conversion into (18)F-FDG-6-phosphate within 30 min. Tumor cells showed significant uptake of (18)F-FDM with time in vitro, and uptake was dose-dependently inhibited by d-glucose. (18)F-FDM injected into tumor-bearing rats showed greater uptake in tumors (2.17 ± 0.32 percentage injected dose per gram [%ID/g]) than in the brain (1.42 ± 0.10 %ID/g) at 60 min after injection. PET studies also revealed the tumor uptake of (18)F-FDM (quasi-standardized uptake value, 2.83 ± 0.22) to be the same as that of (18)F-FDG (2.40 ± 0.30), but the brain uptake of (18)F-FDM (1.89 ± 0.13) was ≈30% lower than that of (18)F-FDG (2.63 ± 0.26). We prepared (18)F-FDM with good radiochemical yield and purity by an SN2 reaction. We demonstrated that (18)F-FDM had adequate tumor cell uptake by a metabolic trapping mechanism and can afford high-contrast tumor images with less uptake in the brain, indicating that (18)F-FDM has almost the same potential as (18)F-FDG for PET tumor imaging, with better advantages with regard to the imaging of brain tumors.
    Journal of Nuclear Medicine 07/2013; · 5.77 Impact Factor
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    ABSTRACT: BACKGROUND: The biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F]FACT) was investigated in humans. METHODS: Six healthy subjects (three males and three females) were enrolled in this study. An average of 160.8 MBq of [18F]FACT was intravenously administered, and then a series of whole-body PET scans were performed. Nineteen male and 20 female source organs, and the remainder of the body, were studied to estimate time-integrated activity coefficients. The mean absorbed dose in each target organ and the effective dose were estimated from the time-integrated activity coefficients in the source organs. Biodistribution data from [18F]FACT in mice were also used to estimate absorbed doses and the effective dose in human subjects; this was compared with doses of [18F]FACT estimated from human PET data. RESULTS: The highest mean absorbed doses estimated using human PET data were observed in the gallbladder (333 +/- 251 muGy/MBq), liver (77.5 +/- 14.5 muGy/MBq), small intestine (33.6 +/- 30.7 muGy/MBq), upper large intestine (29.8 +/- 15.0 muGy/MBq) and lower large intestine (25.2 +/- 12.6 muGy/MBq). The average effective dose estimated from human PET data was 18.6 +/- 3.74 muSv/MBq. The highest mean absorbed dose value estimated from the mouse data was observed in the small intestine (38.5 muGy/MBq), liver (25.5 muGy/MBq) and urinary bladder wall (43.1 muGy/MBq). The effective dose estimated from the mouse data was 14.8 muSv/MBq for [18F]FACT. CONCLUSIONS: The estimated effective dose from the human PET data indicated that the [18F]FACT PET study was acceptable for clinical purposes.
    EJNMMI research. 04/2013; 3(1):32.
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    ABSTRACT: PURPOSE: The aims of this study were to evaluate the binding and pharmacokinetics of novel (18)F-labeled ethenyl-benzoxazole derivatives (i.e., [(18)F] fluorinated amyloid imaging compound of Tohoku university ([(18)F]FACT)) as amyloid positron emission tomography (PET) tracers and to assess [(18)F]FACT efficacy in imaging of Alzheimer's disease (AD). PROCEDURES: Binding assay was conducted using synthetic amyloid-β (Aβ) fibrils, fluorescence microscopy, and autoradiogram in three postmortem AD brains. Pharmacokinetics of [(18)F]FACT was assessed using 12 Crj:CD-1 (ICR) mice. In vivo binding ability with brain amyloid was investigated using amyloid precursor protein (APP) transgenic mouse. Clinical PET scanning using [(18)F]FACT was performed in ten healthy controls and ten mild cognitive impairment and ten AD patients. RESULTS: [(18)F]FACT showed high binding affinity for synthetic Aβ fibrils, preferential binding to dense cored plaques in brain sections, and excellent brain uptake and rapid clearance in mice. Injection in APP mice resulted in specific in vivo labeling of amyloid deposits in the brain. PET scans of AD patients showed significantly higher [(18)F]FACT uptake in the neocortex compared to controls (P < 0.05, Kruskal-Wallis test). CONCLUSION: [(18)F]FACT is a promising agent for imaging dense Aβ plaques in AD.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 01/2013; · 2.47 Impact Factor
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    ABSTRACT: PURPOSE: Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer's disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [(18)F]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [(18)F]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue. METHODS: In vitro radioligand binding assays were conducted using synthetic amyloid β(42) and K18ΔK280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2 μM. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain. RESULTS: [(18)F]THK-523 showed higher affinity for tau fibrils than for Aβ fibrils, whereas the other probes showed a higher affinity for Aβ fibrils. The autoradiographic analysis indicated that [(18)F]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF-227 accumulated in the regions containing a high density of Aβ plaques. CONCLUSION: These findings suggest that the unique binding profile of [(18)F]THK-523 can be used to identify tau deposits in AD brain.
    European Journal of Nuclear Medicine 10/2012; · 4.53 Impact Factor
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    ABSTRACT: Immuno-PET is a promising approach for improved cancer diagnosis, by taking advantage of the high specificity of antibodies. Here, we present a novel cell-free protein synthesis method for preparing a positron emitter labeled-antibody. Functional anti-human EGFRvIII single chain Fv, MR1-1, was successfully labeled with carbon-11 (half-life=20.4min) in 5min (36% yield) by the direct incorporation of the clinical PET tracer, l-[(11)C]methionine. The product [(11)C]MR1-1 was easily and rapidly isolated with high radiochemical purity (>95%) from the reaction solution, by affinity purification. This method would be widely applicable to the preparation of radiolabeled antibodies for PET imaging.
    Bioorganic & medicinal chemistry 09/2012; 20(22):6579-82. · 2.82 Impact Factor
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    ABSTRACT: Aim:  Although diabetes mellitus (DM) is considered to be one of the most consistent risks for developing dementia, it is not known if the pathology in dementia patients with DM is similar to or distinct from typical pathological features of Alzheimer's disease (AD). To discover the mechanism of developing dementia in AD patients with DM in a living state, we studied the distribution of amyloid β (Αβ) protein of diabetic AD patients. Methods:  To evaluate the accumulation of Aβ, we examined 14 normal controls, four diabetic patients with AD and 11 non-diabetic patients with AD by positron emission tomography (PET) using BF-227, a currently developed Aβ tracer. Results:  The analysis of PET images among the three groups showed an abundant aggregated Aβ accumulation in the cerebral cortex of both AD patients with and without DM. The extent and distributions of BF-227 accumulation in diabetic AD patients were not significantly different from these of non-diabetic AD patients. Conclusion:  These results suggest that the degree and extent of Aβ deposition is not significantly different between AD with DM and AD alone. Geriatr Gerontol Int 2012; ••: ••-••.
    Geriatrics & Gerontology International 06/2012;
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    ABSTRACT: Spatial distributions of principal elements in a NFSa fibrosarcoma tumor treated with a vascular disruption agent, AVE8062 (a derivative of combretastatin A-4) at a single dose of 40 mg/kg were evaluated on the basis of particle-induced X-ray emission (PIXE) analysis using a submillimeter-sized proton beam. We found not only potassium and sulfur concentrations at the periphery of the treated tumor but also a ring-shaped calcium distribution in the area between the inner necrotic region and the periphery. These observations were supported by results for quantitative evaluation of elemental concentrations in the tumor samples obtained from conventional PIXE analysis based on the internal standard method. It is suggested that the potassium and sulfur concentrations are related to residual viable cells at the tumor periphery which are commonly observed in VDA treatments whereas the ring of calcium concentration just inside the tumor periphery is possibly derived from hypoxia-induced response.
    International Journal of PIXE 04/2012; 21(03n04).
  • Circulation 01/2012; 125(3):556-7. · 15.20 Impact Factor
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    ABSTRACT: In order to demonstrate the usefulness of electrochemically concentrated [(18)F]fluoride the reactivity of the [K(+)/K.222] (18)F(-) complex concentrated in an aprotic solvent (ca. 60μL) was evaluated via nucleophilic (18)F-substitution reactions through radiosynthesis of [(18)F]FDG, [(18)F]FMISO, [(18)F]flumazenil and [(18)F]fluoromethyl bromide. The substitutions were carried out in a microfluidic reaction flow cell and the effects of reaction time, temperature, precursor concentration and reaction solvent on the (18)F-substitution yields were investigated. The (18)F-fluorination yields for the four (18)F-labeled compounds under optimized conditions (98% for protected [(18)F]FDG, 80% for protected [(18)F]FMISO, 20% for [(18)F]flumazenil and 60% for [(18)F]fluoromethyl bromide) were comparable to or higher than those obtained by conventional means. In this study it is clearly demonstrated that electrochemically concentrated [(18)F]fluoride enables microfluidic radiosynthesis by effectively reducing synthesis times and especially by increasing radiochemical yields of products labile at high temperatures.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 01/2012; 70(1):193-9. · 1.09 Impact Factor
  • Nippon rinsho. Japanese journal of clinical medicine 10/2011; 69 Suppl 8:556-60.

Publication Stats

838 Citations
181.51 Total Impact Points

Institutions

  • 2002–2013
    • Tohoku University
      • • Department of Pharmacology
      • • Department of Diagnostic Radiology
      • • Institute of Development, Aging and Cancer
      • • Graduate School of Engineering
      Sendai, Kagoshima, Japan
  • 2009–2011
    • University of Melbourne
      • Department of Pathology
      Melbourne, Victoria, Australia
  • 2006
    • Sagamihara National Hospital
      Йокосука, Kanagawa, Japan