Hideo Saji

Kyoto University, Kioto, Kyōto, Japan

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Publications (438)1142.14 Total impact

  • Dyes and Pigments 02/2015; 113:205–209. · 3.53 Impact Factor
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    ABSTRACT: In vivo imaging of β-amyloid (Aβ) plaques by non-invasive techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) may facilitate early diagnosis and drug discovery for the treatment of Alzheimer's disease (AD). SPECT is known as a more useful modality than PET in terms of routine diagnostic use, but there have been no reports on attractive probes in clinical studies. In this study, we synthesized and evaluated novel 123I-labeled pyridyl benzoxazole (PBOX) derivatives as SPECT probes for imaging Aβ plaques in vivo. The PBOX derivatives showed affinity for Aβ(1–42) aggregates in vitro (Ki = 6.9–138 nM). In biodistibution experiments in normal mice, all these derivatives showed high initial uptake into (4.6–6.6% ID g−1 at 2 min) and rapid clearance (0.3–1.3% ID g−1 at 60 min) from the brain. Furthermore, [125I]9 clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD brain sections. SPECT/CT study with [123I]9 displayed higher radioactivity in Tg2576 mice than wild-type mice. In addition, ex vivo autoradiograms of brain sections from Tg2576 mice after the injection of [123I]9 showed selective binding of Aβ plaques. In conclusion, [123I]9 may be a potential SPECT probe for imaging Aβ plaques in AD brain.
    RSC Advances 12/2014; 5(2). · 3.71 Impact Factor
  • Masahiro Ono, Hideo Saji
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    ABSTRACT: In this review, we introduce recent advances in our development of molecular imaging probes for positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging for the detection of β-amyloid plaques in the brains of patients with Alzheimer's disease.
    Medicinal Chemistry Communication 11/2014; · 2.72 Impact Factor
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    ABSTRACT: Fluorine-18 labeled radiotracers, such as [18F]fluorodeoxyglucose, can be used as practical diagnostic agents in positron emission tomography (PET). Furthermore, the properties of pharmaceuticals can be enhanced significantly by the introduction of fluorine groups into their original structures, and significant progress has been made during the last three decades towards the development of practical procedures for the introduction of fluorine. The replacement of the fluorine atoms present in pharmaceuticals with radioactive 18F atoms is a rational approach for designing novel PET tracers. As a fluorine-containing pharmaceutical agent, pitavastatin has attracted considerable interest from researchers working in the life sciences because it can act as an antihyperlipidemic agent as well as being a substrate for hepatic organic anion transporting polypeptides (hOATP). With this in mind, it was envisaged that [18F]pitavastatin would be used an excellent imaging agent for hOATP, which prompted us to investigate the synthesis of this agent. Herein, we report a practical method for the synthesis of [18F]pitavastatin by the Suzuki coupling reaction of p-iodofluorobenzene and a quinoline boronate derivative, with the desired product being formed in a radiochemical yield of 12 ± 3 % (decay corrected from [18F]fluoride ion, n = 3).
    Organic & Biomolecular Chemistry 11/2014; · 3.57 Impact Factor
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    ABSTRACT: We previously succeeded in the visualization of tissue distribution of B16BL6 cells-derived exosomes by labeling with Gaussia luciferase (gLuc)-LA, a fusion protein of gLuc (a reporter protein) and lactadherin (LA; an exosome-tropic protein). However, total amount of B16BL6-derived exosomes delivered to each organ could not be evaluated because of the reduction of luminescent signal from gLuc-LA. The aim of the present study was to quantitatively evaluate the tissue distribution of B16BL6-derived exosomes. To this end, we labeled B16BL6-derived exosomes with iodine-125 ((125) I) based on streptavidin (SAV)-biotin system. A plasmid vector encoding fusion protein, SAV-LA, was constructed, and B16BL6 cells were transfected with the plasmid to obtain SAV-LA-coupled exosomes. SAV-LA-coupled exosomes were incubated with (3-(125) I-iodobenzoyl) norbiotinamide ((125) I-IBB) to obtain (125) I-labeled B16BL6 exosomes. After intravenous injection of (125) I-labeled B16BL6 exosomes into mice, radioactivity quickly disappeared from the blood circulation. At 4 h, 28%, 1.6%, and 7% of the injected radioactivity/organ was detected in the liver, spleen, and lung, respectively. These results indicate that (125) I-labeling of exosomes using SAV-biotin system is a useful method to quantitatively evaluate the amount of exogenously administered exosomes delivered to each organ and that the liver is the major organ in the clearance of exogenously administered B16BL6-derived exosomes. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 11/2014; · 3.13 Impact Factor
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    ABSTRACT: Cancer-associated adipocytes metabolically interact with adjacent cancer cells to promote tumor proliferation and metastasis. Fatty acid binding protein 4 (FABP4) participates in this interaction, and is gathering attention as a therapeutic and diagnostic target. Positron emission tomography (PET) is a useful diagnostic method that enables noninvasive in vivo quantitative imaging of biofunctional molecules with probes labeled with positron-emitting radioisotopes. Here a novel 18F labeled probe for PET FABP4 imaging developed through dedicated drug design from a radioiodinated probe we recently reported is evaluated in vitro and in vivo.Methods We designed the [18F]-labeled FTAP1 and FTAP3 probe, composed of a single or triple oxyethylene linker and a triazolopyrimidine scaffold derived from an FABP4 inhibitor. FABP4 binding affinities for chemically synthesized FTAP1 and FTAP3 were measured using FABP4 and 8-anilino-1-naphthalene sulfonic acid. Cell membrane permeability was measured using a commercially available plate assay system. After radiosynthesis, [18F]FTAP1 affinity and selectivity were evaluated using immobilized FABP3, FABP4, and FABP5. Cell uptake was investigated using differentiated adipocytes expressing FABP4 with inhibitor treatment. Following biodistribution studies in C6 glioblastoma-bearing mice, ex vivo autoradiography and immunohistochemistry were performed using thin sliced tumor sections. PET/CT imaging was then performed on C6 tumor bearing mice.ResultsFTAP1 showed high FABP4 affinity (Ki = 68 ± 8.9 nM) and adequate cell permeability. [18F]FTAP1 with ≥ 98% radiochemical purity was shown to selectively bind to FABP4 (16.3- and 9.3-fold higher than for FABP3 and FABP5, respectively). [18F]FTAP1 was taken up by FABP4 expressing cells, and this uptake could be blocked by an inhibitor, indicating very low non-specific cell binding. [18F]FTAP1 showed high tumor accumulation, which demonstrates its potential use for in vivo tumor PET imaging, and the intratumoral radioactivity distribution corresponded to the FABP4 expression profile.Conclusion[18F]FTAP1 is a promising PET probe to target FABP4.
    Nuclear Medicine and Biology. 10/2014;
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    ABSTRACT: Styryl-congutated BODIPY dyes which are structurally similar to known Aβ peptide binding dyes, were designed and synthesized. The binding is accompanied by a large increase in the emission intensity in all cases, suggesting a high potential for use in the fluorescence imaging of Aβ plaques.
    RSC Advances 10/2014; 4(92). · 3.71 Impact Factor
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    ABSTRACT: This letter describes a 68Ga complex based on benzofuran scaffold for the detection of b-Amyloid Plaques.
    Bioorganic & Medicinal Chemistry Letters 09/2014; · 2.34 Impact Factor
  • Journal of Biomedical Optics 09/2014; 19(9):96002. · 2.75 Impact Factor
  • Journal of Biomedical Optics 09/2014; 19(9):90501. · 2.75 Impact Factor
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    ABSTRACT: Microwave technology has been successfully applied to enhance the effectiveness of radiolabeling reactions. The use of a microwave as a source of heat energy can allow chemical reactions to proceed over much shorter reaction times and in higher yields than they would do under conventional thermal conditions. A microwave reactor developed by Resonance Instrument Inc. (Model 520/521) and CEM (PETWave) has been used exclusively for the synthesis of radiolabeled agents for positron emission tomography by numerous groups throughout the world. In this study, we have developed a novel resonant-type microwave reactor powered by a solid-state device and confirmed that this system can focus microwave power on a small amount of reaction solution. Furthermore, we have demonstrated the rapid and facile radiosynthesis of 16α-[18F]fluoroestradiol, 4-[18F]fluoro-N-[2-(1-methoxyphenyl)-1-piperazinyl]ethyl-N-2-pyridinylbenzamide, and N-succinimidyl 4-[18F]fluorobenzoate using our newly developed microwave reactor.
    Journal of Labelled Compounds 09/2014;
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    ABSTRACT: Islet amyloid deposition composed of amylin aggregates is regarded as one of the hallmarks of type 2 diabetes mellitus (T2DM). For the diagnosis of T2DM, several nuclear medical imaging probes have been developed. However, there have been no reports regarding the development of imaging probes targeting amylin. In this report, we investigated the feasibility of amylin imaging using [(125)I]IPBF as one of the model compounds of β-amyloid (Aβ) imaging probes. In in vitro experiments, [(125)I]IPBF exhibited high binding affinity for amylin aggregates (Kd = 8.31 nM). Moreover, autoradiographic images showed that [(125)I]IPBF specifically bound to islet amyloid composed of amylin. These results suggest the potential application of Aβ imaging probes to amylin imaging. In addition, [(125)I]IPBF is one of the promising lead compounds for amylin imaging, and further structural optimization based on [(125)I]IPBF may lead to useful tracers for the in vivo imaging of islet amyloids in the pancreas.
    Scientific Reports 08/2014; 4:6155. · 5.08 Impact Factor
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    ABSTRACT: We aimed to develop a gallium-68 (Ga-68)-labeled single-chain variable fragment (scFv) targeting the human epidermal growth factor receptor 2 (HER2) to rapidly and noninvasively evaluate the status of HER2 expression.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 07/2014; · 2.47 Impact Factor
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    ABSTRACT: Membrane type-1 matrix metalloproteinase (MT1-MMP) is a protease activating MMP-2 that mediates cleavage of extracellular matrix components and plays pivotal roles in tumor migration, invasion, and metastasis. Since in vivo noninvasive imaging of MT1-MMP would be useful for tumor diagnosis, we developed a novel near-infrared (NIR) fluorescence probe that can be activated following interaction with MT1-MMP in vivo. MT1-hIC7L is an activatable fluorescence probe comprised of anti-MT1-MMP monoclonal antibodies conjugated to self-assembling polymer micelles that encapsulate NIR dyes (IC7-1, λem: 858 nm) at concentrations sufficient to cause fluorescence self-quenching. In aqueous buffer, MT1-hIC7L fluorescence was suppressed to background levels and increased approximately 35.5-fold in the presence of detergent. Cellular uptake experiments revealed that in MT1-MMP positive C6 glioma cells, MT1-hIC7L showed significantly higher fluorescence that increased with time as compared to hIC7L, a negative control probe lacking the anti-MT1-MMP monoclonal antibody. In MT1-MMP negative MCF-7 breast adenocarcinoma cells, both MT1-hIC7L and hIC7L showed no obvious fluorescence. In addition, the fluorescence intensity of C6 cells treated with MT1-hIC7L was suppressed by pre-treatment with a MT1-MMP endocytosis inhibitor (p < 0.05). In vivo optical imaging using probes intravenously administered to tumor bearing mice showed that MT1-hIC7L specifically visualized C6 tumors (tumor-to-background ratios: 3.8 ± 0.3 (MT1-hIC7L) vs. 3.1 ± 0.2 (hIC7L) 48 h after administration, p < 0.05), while the probes showed similarly low fluorescence in MCF-7 tumors. Together, these results show that MT1-hIC7L would be a potential activatable NIR probe for specifically detecting MT1-MMP expressing tumors.This article is protected by copyright. All rights reserved.
    Cancer Science 05/2014; · 3.48 Impact Factor
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    ABSTRACT: The genetic transfer of T-cell receptors (TCRs) directed toward target antigens into T lymphocytes has been used to generate antitumor T cells efficiently without the need for the in vitro induction and expansion of T cells with cognate specificity. Alternatively, T cells have been gene-modified with a TCR-like antibody or chimeric antigen receptor (CAR). We show that immunization of HLA-A2 transgenic mice with tetramerized recombinant HLA-A2 incorporating HA-1 H minor histocompatibility antigen (mHag) peptides and β2-microglobulin (HA-1 H/HLA-A2) generate highly specific antibodies. One single-chain variable region moiety (scFv) antibody, #131, demonstrated high affinity (KD=14.9 nM) for the HA-1 H/HLA-A2 complex. Primary human T cells transduced with #131 scFV coupled to CD28 transmembrane and CD3ζ domains were stained with HA-1 H/HLA-A2 tetramers slightly more intensely than a cytotoxic T lymphocyte (CTL) clone specific for endogenously HLA-A2- and HA-1 H-positive cells. Although #131 scFv CAR-T cells required >100-fold higher antigen density to exert cytotoxicity compared with the cognate CTL clone, they could produce inflammatory cytokines against cells expressing HLA-A2 and HA-1 H transgenes. These data implicate that T cells with high-affinity antigen receptors reduce the ability to lyse targets with low-density peptide/MHC complexes (~100 per cell), while they could respond at cytokine production level.Gene Therapy advance online publication, 3 April 2014; doi:10.1038/gt.2014.30.
    Gene therapy 04/2014; · 4.75 Impact Factor
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    ABSTRACT: Mitochondrial membrane potential (Δψm) alteration is an important target for cancer diagnosis. In this study, we designed a series of near-infrared fluorescent cationic cyanine dyes with varying alkyl chain lengths (IC7-1 derivatives) to provide diverse lipophilicities and serum albumin-binding rates, and we evaluated the usefulness of these derivatives for in vivo Δψm imaging. IC7-1 derivatives with side chains from methyl to hexyl (IC7-1-Me to IC7-1-He) were synthesized, and their optical properties were measured. Cellular uptake and intracellular distribution were investigated with depolarized HeLa cells from carbonyl cyanine m-chlorophenylhydrazone (CCCP) treatment using a spectrofluorometer and a fluorescence microscope. Serum albumin-binding rates were evaluated using albumin-binding inhibitors. In vivo optical imaging was performed with HeLa cell xenograft mice following intravenous administration of IC7-1 derivatives with or without warfarin and CCCP as in vivo blocking agents. IC7-1 derivatives showing maximum excitation and emission wavelengths at 823 nm and ~845 nm, respectively, were synthesized. IC7-1-Me to -Bu showed fluorescence in mitochondria that decreased with CCCP treatment in a concentration-dependent manner, which showed that IC7-1-Me to -Bu successfully indicated Δψm. Tumors were clearly visualized after IC7-1-Bu administration. Treatment with warfarin or CCCP significantly decreased IC7-1-Bu fluorescence in the tumor region. In summary, IC7-1-Bu exhibited fluorescence localized to mitochondria dependent on Δψm, which enabled clear in vivo tumor imaging via serum albumin as a drug carrier for effective tumor targeting. Our data suggest that IC7-1-Bu is a promising NIR probe for in vivo imaging of the altered Δψm of tumor cells.
    Cancer Medicine 04/2014;
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    ABSTRACT: Deposition of amyloid aggregates has been regarded as an early stage of amyloidosis progression. An imaging probe that can image amyloid aggregates enables the early diagnosis of amyloidosis and contributes to the development of new medical therapies. High binding affinity for amyloid aggregates is essential to develop a useful molecular imaging probe. This article describes a new strategy to enhance the binding affinity of imaging agents targeting amyloid aggregates. We designed and synthesized novel (99m)Tc-hydroxamamide ((99m)Tc-Ham) complexes with a bivalent amyloid ligand and evaluated their binding affinity for amyloid aggregates by using β-amyloid peptide (Aβ(1-42)) aggregates as a model. In vitro inhibition assay indicated that bivalent (99m)Tc-Ham complexes had much higher binding affinity for amyloid aggregates than monovalent complexes. In vitro autoradiography using Tg2576 mice showed the specific binding of bivalent (99m)Tc-Ham complexes to Aβ plaques in the mouse brain, as reflected in the results of the inhibition assay. The preliminary results suggest that a new molecular design based on bivalent (99m)Tc-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates.
    Molecular Pharmaceutics 03/2014; · 4.57 Impact Factor
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    ABSTRACT: We have developed a novel radiogallium (Ga)-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging. A CXCR4 imaging probe with two CXCR4 antagonists (Ac-TZ14011) on Ga-DOTA core, Ga-DOTA-TZ2, was synthesized, and the affinity and binding to CXCR4 was evaluated in CXCR4 expressing cells in vitro. The affinity of Ga-DOTA-TZ2 for CXCR4 was 20-fold greater than the corresponding monovalent probe, Ga-DOTA-TZ1. 67Ga-DOTA-TZ2 showed the significantly higher accumulation in CXCR4-expressing tumor cells compared with 67Ga-DOTA-TZ1, suggesting the bivalent effect enhances its binding to CXCR4. The incorporation of two CXCR4 antagonists to Ga-DOTA could be effective in detecting CXCR4-expressing tumors.
    Bioorganic & medicinal chemistry letters 03/2014; · 2.65 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-related death. Since significant upregulation of αvβ6 integrin has been reported in PDAC, this integrin is a promising target for PDAC detection. In this study, we aimed to develop a radioiodinated probe for the imaging of αvβ6 integrin-positive PDAC with single-photon emission computed tomography (SPECT). Four peptide probes were synthesized and screened by competitive and saturation binding assays using 2 PDAC cell lines (AsPC-1, αvβ6 integrin-positive; MIA PaCa-2, αvβ6 integrin-negative). The probe showing the best affinity was used to study the biodistribution assay, an in vivo blocking study, and SPECT imaging using tumor bearing mice. Autoradiography and immunohistochemical analysis were also performed. Among the 4 probes examined in this study, (125)I-IFMDV2 showed the highest affinity for αvβ6 integrin expressed in AsPC-1 cells and no affinity for MIA PaCa-2 cells. The accumulation of (125)I-IFMDV2 in the AsPC-1 xenograft was 3-5 times greater than that in the MIA PaCa-2 xenograft, consistent with the expression of αvβ6 integrin in each xenograft, and confirmed by immunohistochemistry. Pretreatment with excess amounts of A20FMDV2 significantly blocked the accumulation of (125)I-IFMDV2 in the AsPC-1 xenograft, but not in the MIA PaCa-2 xenograft. Furthermore, (123)I-IFMDV2 enabled clear visualization of the AsPC-1 xenograft. (123)I-IFMDV2 is a potential SPECT probe for the imaging of αvβ6 integrin in PDAC.
    Biochemical and Biophysical Research Communications 02/2014; · 2.28 Impact Factor
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    ABSTRACT: The deposition of β-amyloid (Aβ) plaques in the parenchymal and cortical brain is accepted as the main pathological hallmark of Alzheimer's disease (AD); however, early detection of AD still presents a challenge. With the assistance of molecular imaging techniques, imaging agents specifically targeting Aβ plaques in the brain may lead to the early diagnosis of AD. Herein, we report the design, synthesis, and evaluation of a series of smart near-infrared fluorescence (NIRF) imaging probes with donor-acceptor architecture bridged by a conjugated π-electron chain for Aβ plaques. The chemical structure of these NIRF probes is completely different from Congo Red and Thioflavin-T. Probes with a longer conjugated π system (carbon-carbon double bond) displayed maximum emission in PBS (>650 nm), which falls in the best range for NIRF probes. These probes were proved to have affinity to Aβ plaques in fluorescent staining of brain sections from an AD patient and double transgenic mice, as well as in an in vitro binding assay using Aβ1-42 aggregates. One probe with high affinity (Ki = 37 nM, Kd = 27 nM) was selected for in vivo imaging. It can penetrate the blood-brain barrier of nude mice efficiently and is quickly washed out of the normal brain. Moreover, after intravenous injection of this probe, 22-month-old APPswe/PSEN1 mice exhibited a higher relative signal than control mice over the same period of time, and ex vivo fluorescent observations confirmed the existence of Aβ plaques. In summary, this probe meets most of the requirements for a NIRF contrast agent for the detection of Aβ plaques both in vitro and in vivo.
    Journal of the American Chemical Society 02/2014; · 10.68 Impact Factor

Publication Stats

4k Citations
1,142.14 Total Impact Points


  • 1978–2014
    • Kyoto University
      • • Division of Pharmaceutical Sciences
      • • Graduate School of Pharmaceutical Sciences / Faculty of Pharmaceutical Sciences
      • • Radioisotope Research Laboratory
      • • Department of Diagnostic Imaging and Nuclear Medicine
      • • Department of Cardiovascular Medicine
      Kioto, Kyōto, Japan
  • 2004–2013
    • Hokkaido University
      • Department of Internal Medicine II
      Sapporo, Hokkaidō, Japan
    • Ibaraki Prefectural University of Health Sciences
      • Department of Radiological Sciences
      Ibaragi, Ōsaka, Japan
  • 1991–2013
    • Kyoto Pharmaceutical University
      • Laboratory of Pharmaceutical Manufacturing Chemistry
      Kioto, Kyōto, Japan
  • 2012
    • Shionogi & Co., Ltd.
      Ōsaka, Ōsaka, Japan
  • 2011–2012
    • Hyogo College of Medicine
      • Department of Internal Medicine
      Nishinomiya, Hyogo-ken, Japan
    • Daiichi Sankyo Company
      • Division of Research and Development
      Tokyo, Tokyo-to, Japan
    • Alexandrovska University Hospital
      Ulpia Serdica, Sofia-Capital, Bulgaria
    • Kobe Pharmaceutical University
      Kōbe, Hyōgo, Japan
  • 1998–2012
    • Nagasaki University
      • • Faculty of Environmental Studies
      • • Department of Hygienic Chemistry
      • • Graduate School of Biomedical Sciences
      • • Department of Basic Pharmaceutical Sciences
      Nagasaki, Nagasaki, Japan
  • 2009–2011
    • Kanazawa University
      • • Graduate School of Natural Science and Technology
      • • Advanced Science Research Center
      Kanazawa-shi, Ishikawa-ken, Japan
  • 2005–2008
    • University of Fukui
      • Biomedical Imaging Research Center
      Hukui, Fukui, Japan
  • 2007
    • Chiba University
      • Graduate School of Pharmaceutical Sciences
      Chiba-shi, Chiba-ken, Japan
  • 2006
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
  • 2003–2006
    • Hamamatsu University School of Medicine
      • Medical Photonics Research Center
      Hamamatu, Shizuoka, Japan
    • The Institute for Research and Development
      Ajni, Mahārāshtra, India
    • Osaka City University
      • Department of Neurosurgery
      Ōsaka, Ōsaka, Japan
  • 2001–2006
    • Okayama University
      • • Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
      • • Faculty of Pharmaceutical Science
      Okayama-shi, Okayama-ken, Japan
  • 2004–2005
    • Miyazaki University
      • Department of Psychiatry
      Миядзаки, Miyazaki, Japan
  • 2003–2004
    • National Cerebral and Cardiovascular Center
      • Department of Cardiovascular Medicine
      Ōsaka, Ōsaka, Japan
  • 2001–2002
    • Kyoto Prefectural University of Medicine
      Kioto, Kyōto, Japan
  • 1997–2000
    • Kyoto Daini Red Cross Hospital
      Kioto, Kyōto, Japan
  • 1999
    • Toyama Medical and Pharmaceutical University
      Тояма, Toyama, Japan
  • 1993–1996
    • Japanese Red Cross
      Edo, Tōkyō, Japan
  • 1995
    • Shiga University of Medical Science
      • Department of Radiology
      Ōtu, Shiga, Japan
  • 1990–1995
    • Tokyo University of Science
      • Department of Pharmaceutical Sciences
      Tokyo, Tokyo-to, Japan
  • 1986
    • National Institute of Radiological Sciences
      Tiba, Chiba, Japan