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| 1.
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Ogawa, Kazuma ; Takai, Kenichiro ; Kanbara, Hiroya ; Kiwada, Tatsuto ; Kitamura, Youji ; Shiba, Kazuhiro ; Odani, Akira
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金沢大学医薬保健研究域薬学系<br />Introduction: 68Ga is a radionuclide of great interest as a positron emitter for positron emission t
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omography (PET). To develop a new bone-imaging agent with radiogallium, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as a chelating site and Ga-DOTA complex-conjugated bisphosphonate, which has a high affinity for bone, was prepared and evaluated. Although we are interested in developing 68Ga-labeled bone imaging agents for PET, in these initial studies 67Ga was used because of its longer half-life. Methods: DOTA-conjugated bisphosphonate (DOTA-Bn-SCN-HBP) was synthesized by conjugation of 2-(4-isothiocyanatebenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). 67Ga-DOTA-Bn-SCN-HBP was prepared by coordination with 67Ga, and its in vitro and in vivo evaluations were performed. Results: 67Ga-DOTA-Bn-SCN-HBP was prepared with a radiochemical purity of over 95% without purification. 67Ga-DOTA-Bn-SCN-HBP had great affinity for hydroxyapatite in binding assay. In biodistribution experiments, 67Ga-DOTA-Bn-SCN-HBP accumulated in bone rapidly but was hardly observed in tissues other than bone. Pretreatment of an excess amount of alendronate inhibited the bone accumulation of 67Ga-DOTA-Bn-SCN-HBP. Conclusions: 67Ga-DOTA-Bn-SCN-HBP showed ideal biodistribution characteristics as a bone-imaging agent. These findings should provide useful information on the drug design of bone imaging agents for PET with 68Ga. © 2010 Elsevier Inc. All rights reserved.
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| 2.
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Noda, Akihiro ; Takamatsu, Hiroyuki ; Murakami, Yoshihiro ; Yajima, Kazuyoshi ; Tatsumi, Mitsuyoshi ; Ichise, Rikiya ; Nishimura, Shintaro
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金沢大学大学院医学系研究科<br />This study used PET to measure the time course of the brain concentration of 18F-labeled N-(4-acetyl-
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1-piperazinyl)-p-fluorobenzamide monohydrate (FK960), a novel antidementia drug, after oral administration to conscious rhesus monkeys. Methods: Three young-adult male rhesus monkeys were tested. FK960 (0.1 mg/kg) containing about 370 MBq of 18F-FK960 was administered orally to each monkey. Dynamic PET images were acquired for 4 h from 5 min after the administration. Arterial blood samples were withdrawn during PET scanning and were analyzed by an automatic well γ-counter and thin-layer chromatography to determine the time course of authentic 18F-FK960 activity concentration in plasma. FK960 concentrations in brain and plasma were calculated in units of mol/L using the specific activity of FK960 preparations. Results: 18F-FK960 penetrated the blood-brain barrier and underwent perfusion-dependent distribution in the entire brain. Maximal concentrations in the brain and plasma were 1.11 ± 0.30 x 10-7 mol/L (at 3.0 ± 0.6 h after administration) and 4.04 ± 1.29 x 10-7 mol/L (at 2.0 ± 1.1 h after administration), respectively. Conclusion: We succeeded in measuring the FK960 concentration in the brains of conscious monkeys and in plasma after oral administration at a dose of 0.1 mg/kg. The results suggested that this method can measure the FK960 concentration in the human brain, and a potential use of the PET technique in drug development was demonstrated.
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| 3.
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山田, 敏郎 ; 那須, 礼学 ; 岩崎, 貴之 ; 杉原, 元樹
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An uneven thickness distribution can cause serious problems in practical applications. In this report the deformation and thickness behavior of poly (ethylene terephthalate) (PET) film during transverse stretching in a tenter is
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discussed. The experiments were performed in a pilot plant with extrusion, casting, machine direction (MD) stretching, transverse direction (TD) stretching and thermosetting and winding processes. The thickness distribution of the PET film was measured after uniaxial orientation (MD stretched) and again after biaxial orientation (TD stretched in the tenter). The thickness behavior during the transverse stretching in the tenter was calculated by a finite element method (FEM), assuming a rigid-plastic or elastic-plastic constitutive law with parameters determined from the tensile stress-strain measurements. The tensile stress-strain tests were performed on MD stretched film in the transverse stretching direction. The FEM analysis was carried out using the measured initial thickness distribution of the uniaxially oriented film (MD stretched). It was estimated from this analysis that the (TD) stretching of the film in the tenter initiated near the tenter clip (edge of film), spread to the center of the film and then finally moved from the center to the edge of the film under the experimental conditions of this study. Good agreement was obtained between the experimental and predicted FEM results for the final film thickness distribution after transverse stretching.
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4. A radiobrominated tyrosine kinase inhibitor for egfr with l858r/t790m mutations in lung carcinoma
Fawwaz, Muammar ; Mishiro, Kenji ; Nishii, Ryuichi ; Makino, Akira ; Kiyono, Yasushi ; Shiba, Kazuhiro ; Kinuya, Seigo ; Ogawa, Kazuma ; 三代, 憲司 ; 柴, 和弘 ; 絹谷, 清剛 ; 小川, 数馬
概要:
金沢大学疾患モデル総合研究センター<br />Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are
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often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third‐generation EGFR‐TKIs, such as osimertinib and rociletinib (CO‐1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine‐labeled CO‐ 1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated‐CO1686 (BrCO1686) was synthesized by the condensation of N‐(3‐[{2‐chloro‐5‐(trifluoromethyl)pyrimidin‐4‐yl}amino]‐5‐bromophenyl) acrylamide with the corresponding substituted 1‐(4‐[4‐amino‐3‐methoxyphenyl]piperazine‐1‐yl)ethan‐1‐one. The radi-obrominated [77 Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N‐chlorosuccinimide. Although we aimed to provide a novel PET imaging probe,77Br was used as an alternative radionuclide for76Br. We fun-damentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non‐small‐cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild‐type EGFR). The BrCO1686 showed high cy-totoxicity toward H1975 (IC50 0.18 ± 0.06 μM) comparable to that of CO‐1686 (IC50 0.14 ± 0.05 μM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO‐1686. These results indicate that the binding site of the radiotracers should be identical to that of CO‐1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild‐type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.<br />CC-BY 4.0
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| 5.
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三辺, 義雄 ; Minabe, Yoshio
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金沢大学医薬保健研究域医学系<br />知能障害を有しない自閉症スペクトラム障害者へのオキシトシンの経鼻長期投与による、セロトニン系への影響や、社会的認知機能への影響を調査し、改善する個体の大脳生理学的特徴を検討した。薬剤１０週間投与前後の
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セロトニントランスポーター密度の変化をPETを用いて調べた。試験のデザインは、非ランダム化無対象オープンデザインを用いた。11C-DASB PETの解析においては、１０人中3名において、明らかに、オキシトシン投与後の上昇を認めていた。これらの３名については、STAIの不安症状が軽減していた。オキシトシン投与により、脳内セロトニン系の変化を介して、抗不安効果が表れている可能性が示唆された。<br />With chronic administration of the oxytocin to the patients with autism spectrum disorder who does not have intelligence impairment, we investigated the influence on the serotonin system and the influence on a social cognitive function. The neurophysiological characterization of the patient who improves with oxytocin administration was also explored. We investigated the changes of the serotonin transporter density after the drug treatment (ten weeks), and we also investigated the changes in brain response to social stimuli recorded by MEG. Study desing: Non-randomized, open and uncontrolled.<br />研究課題/領域番号:24390282, 研究期間(年度):2012-04-01 - 2015-03-31
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| 6.
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山田, 正仁 ; Yamada, Masahito
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脳アミロイドアンギオパチー(CAA)関連脳出血リスク評価法およびCAA及びCAA関連脳出血の予防法の開発を行った。CAA例を調査研究し、CAA及びCAA関連血管障害のバイオマーカー、危険因子からなるリスク評価法を提案した。CAAのin vi
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troモデルを構築し、フェノール化合物のAβ線維化・オリゴマー化抑制効果、作用機序を解明した。それらはin vivoモデルにおいてCAAを含む脳アミロイド沈着を抑制した。<br />We investigated cerebral amyloid angiopathy(CAA) and CAA-related hemorrhages to develop methods of risk assessment and prevention. We propose a table of biomarkers and risk factors to predict future development of CAA-related hemorrhages and other disorders. We established an in vitro model of CAA. We revealed that natural phenolic compounds inhibited fibril formation and oligomerization of amyloidβ-protein(Aβ) in in vitro and in vivo models.<br />研究課題/領域番号:20390242, 研究期間(年度):2008-2011
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| 7.
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松尾, 信郎 ; Matsuo, Shinro
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金沢大学附属病院核医学診療科<br />「短時間心筋SPECT/CTによる新しい診断技術の開発」については、虚血性心疾患またはその疑い症例に対して、低エネルギー性コリメータとSMARTZOOMコリメータを用いて心筋血流検査を行った。IQ-S
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PECTシステム短時間撮影による撮影で得られた解析の有用性が示された。「左室位相解析によるリスク層別化」は、位相解析を行って左室同期不全の指標を計測し、位相解析指標の規定因子についての解析が臨床応用できる。「N-13アンモニアによるリスク層別化研究」では、アンモニア合成装置を用いて、N-13アンモニアを合成し、TOF技術による虚血性心疾患の新しい診断技術が利用可能となる。<br />Regarding the development of a new diagnostic technique by myocardial SPECT / CT, Myocardial perfusion test was performed using SMARTZOOM collimator (IQ-SPECT) or low energy collimator. The results of IQ-SPECT system, obtained with short-time acquisition were compared with those of conventional shooting, and the analysis results were shown to be useful for clinical use. In the study "Risk stratification by left ventricular phase analysis", the index of left ventricular dyssynchrony was measured using phase analysis and QGS software which can evaluate left ventricular function. And the factors from phase analysis were validated in patients with coronary artery disease. In the research "Research on risk stratification by N-13 ammonia", N-13 ammonia was synthesized using ammonia synthesizer and the study was performed to develop a new diagnostic technique for ischemic heart disease by TOF technology.<br />研究課題/領域番号:26461846, 研究期間(年度):2014-04-01 - 2017-03-31
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| 8.
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小川, 数馬 ; Ogawa, Kazuma
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癌治療において、抗癌剤を効率良く癌組織に運ぶことにより、癌治療効果を高め、副作用を軽減するdrug delivery system (DDS)は非常に重要である。本研究では骨の無機質の主な構成成分であるハイドロキシアパタイトをナノ粒子輸送担
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体として用いたDDS薬剤の開発を目的に、骨親和性放射性薬剤をハイドロキシアパタイトに結合させた新規癌診断・治療DDSの構築・評価を行った。<br />Drug delivery system (DDS), which is for delivery of anticancer drugs to cancer tissue, is very important because it enhances the therapeutic effects and reduces the side effects. The aim of this study is development of a DDS using hydroxyapatite as a nanoparticle carrier. A novel cancer diagnosis and therapy DDS, which is a conjugation between a radiolabeled compound with high bone affinity and hydroxyapatite, was synthesized and evaluated.<br />研究課題/領域番号:23791401, 研究期間(年度):2011-2012
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小川, 数馬 ; Ogawa, Kazuma
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まず、ビスホスホネートを骨への輸送担体とした^<67>Ga-DOTA conjugatedビスホスホネートを合成し、その錯体の有用性を評価した。^<67>Ga-DOTA conjugatedビスホスホネートは、精製することなく、放射化学的純
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度95%以上で標識でき、マウスにおける体内放射能分布を検討した結果、投与後速やかに骨への高い放射能集積を示し、他の組織からは速やかにクリアランスされ、薬剤の有用性が示された。<br />DOTA-conjugated bisphosphonate was synthesized using bisphosphonate as a carrier to bone. ^<67>Ga-DOTA-conjugated bisphosphonate was prepared with a radiochemical purity of over 95% without purification. In biodistribution experiments, ^<67>Ga-DOTA-conjugated bisphosphonate accumulated in bone rapidly but were hardly observed in tissues other than bone. These results indicate that ^<67>Ga-DOTA-conjugated bisphosphonate has ideal biodistribution characteristics as bone-imaging agents.<br />研究課題/領域番号:21791174, 研究期間(年度):2009-2010
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| 10.
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澁谷, 孝行 ; Shibutani, Takayuki
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金沢大学医薬保健研究域保健学系<br />小動物研究の中で虚血性心疾患の評価に重要な心筋バイアビリティは，別時相で収集されるため，小動物の時相差に伴う生理状態の違いが定量誤差となり，病態と分子情報のミスマッチが生じていた。その問題を解決する
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ために，本研究ではTc-99m心筋血流とF-18の心筋糖代謝情報を対象に本邦初導入された小動物用SPECT・PET同時収集システムを用いて複数分子同時収集における心筋バイアビリティ定量評価法を開発した。小動物を模擬したファントムを新たに開発し，複数分子同時収集で問題となるクロストークによる画質劣化と部分容積効果による定量値の過小評価を改善するための補正技術を確立させた。<br />Myocardial viability evaluation which is important for ischemic heart disease in small animal studies is acquired in different time phases, and it was a mismatch between the pathological condition and the molecular information due to the quantitative error caused by the difference in physiological state caused by the time phase difference of small animals. To resolve this problem, we developed a quantitative evaluation method of myocardial viability in simultaneous acquisition of multiple molecules for Tc-99m myocardial blood flow and F-18 myocardial glucose metabolism using the small animal SPECT/PET simultaneous acquisition system introduced for the first time in Japan.A phantom simulating a small animal was newly developed, and a correction technique was established to improve image quality due to crosstalk and underestimation of quantitative values caused by partial volume effect which are problems in simultaneous acquisition of multiple molecules.<br />研究課題/領域番号:18K15628, 研究期間(年度):2018-04-01 - 2021-03-31<br />出典：「小動物SPECT・PET同時測定法における物理現象の解明と定量評価法の確立」研究成果報告書 課題番号18K15628（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18K15628/18K15628seika/ ）を加工して作成
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