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Toyohara Jun

    PET Radiopharmaceutical Sciences　Vice-director
Last Updated :2025/04/14

Researcher Information

Degree

  • PhD

URL

Research funding number

  • 50425659

J-Global ID

Research Interests

  • 核医学   放射線   癌   薬学   ストレス   チミジンホスホリラーゼ   ヌクレオシド   放射性医薬品   核酸   分子イメージング   分析科学   脳神経疾患   ポジトロンCT   

Research Areas

  • Life sciences / Radiology

Academic & Professional Experience

  • 2023/04 - Today  Tokyo Metropolitan Institute for Geriatrics and GerontologyTokyo Metropolitan Institute of GerontologyChief Researcher
  • 2010/04 - Today  Tokyo Metropolitan Geriatric Hospital and Institute of Gerontologyその他
  • 2007/09 - 2010/03  Chiba UniversityCenter for Forensic Mental Health講師
  • 2005/05 - 2007/08  放射線医学総合研究所分子イメージング研究センター任期付研究員
  • 1993/04 - 2005/04  日本メジフィジックス株式会社創薬研究所研究員

Published Papers

MISC

Industrial Property Rights

Awards & Honors

  • 2017/11 日本核医学会 第56回日本核医学会賞
     
    受賞者: 豊原潤
  • 2017/11 日本核医学会 久田賞銀賞（日本核医学会機関紙論文賞）
     
    受賞者: 豊原潤
  • 2010 日本核医学会 久田賞銀賞（日本核医学会機関誌論文賞）
     
    受賞者: 豊原潤

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2024/03 
    Author : 豊原 潤; 森田 光洋
     
    本研究では、最新の標識化学の知見を活用して、「AQP4に対する高感度かつ選択的な高品質のPET薬剤の実用化」を目的とする。APQに対するPET薬剤として、[11C]TGN-020が提案されているが、比放射能が低く極めて収率が悪い（1%以下）のため、標識合成法の改良を実施した。Bongarzoneらによる、Cu(I)触媒を用いたボロン酸エステルの[11C]カルボキシル化反応を用いて、中間体の[11C]ニコチン酸を合成した。モレキュラーシーブにより[11C]CO2を濃縮した場合、反応容器への[11C]CO2のトラップ率50%、ニコチン酸への反応効率60%で[11C]ニコチン酸が得られた。次のアミド結合生成反応には、第一段階で使用する触媒の影響で反応が進行しなかったため、固相抽出による[11C]ニコチン酸の簡易精製の方法を検討している。 TGN-020は脳脈絡叢に発現するAQP1に対しても親和性があるため、選択性が悪い。一方、これに対して近年報告されたARE-270はTGN-020に比べ、AQP4に対して高い親和性と選択性を有する。そこで、ARE-270のトリフルオロメチル基に着目して、[18F]ARE-270の標識合成を検討した。[18F]ARE-270の標識合成は、Hubianらによる[18F]トリフルオロメチル銅錯体と芳香族ヨウ素化合物のクロスカップリングを用いて[18F]ARE-270の標識合成を計画した。これまでに、サリチル酸とアニリンの酸塩化物を用いた縮合反応で、標準品のARE-270を70%、標識前駆体のヨウ素体を35%の収率で得た。また、[18F]トリフルオロメチル銅錯体と芳香族ヨウ素化合物のクロスカップリング反応についてモデル化合物による検討を実施し、標識可能であることを確認してた。一方、モデル化合物での検討から、Hubianらによる方法では、加熱条件が過酷であるため、基質によっては分解が促進されることも明らかとなった
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2019/04 -2023/03 
    Author : 山本 由佳; 久冨 信之; 西山 佳宏; 豊原 潤; 畠山 哲宗; 則兼 敬志
     
    脳腫瘍にPET分子イメージングを応用し、腫瘍組織の増殖能と低酸素環境を評価する。新たな画像バイオマーカーとしてテクスチャ解析を計画し、腫瘍の形状や内部の特徴量といった性状を数値化する。脳腫瘍のPET検査で腫瘍増殖能と低酸素環境の病態評価を行い、従来の半定量的指標とテクスチャ解析指標を併用することで、悪性度、遺伝子変異予測、予後予測、治療薬の反応性などの判断の向上ができるか否かを明らかにする。 まず、腫瘍組織の増殖能を評価できるF-18 FLT PETを脳腫瘍新鮮例37名に実施した。 脳腫瘍の悪性度・分裂能評価として病理学的にKi-67指標を求めた。PETの評価として、腫瘍と正常大脳のSUVとT/N比、また腫瘍MTVなどを算出した。また、テクスチャ解析による5種類のパラメータ(standard deviation、skewness、kurtosis、entropy、uniformity) を算出した。その結果では脳腫瘍は全例陽性描画された。Ki-67との関係ではT/N比（p=0.02）、MTV（p=0.02）ともに良好な関係を示した。テクスチャー解析によるパラメータの結果では、kurtosis（p=0.030）、entropy（p<0.001）、uniformity（p<0.001）ともにKI-67と良好な関係を示した。さらに、テクスチャ解析から求めた指標は従来の指標であるT/N比やMTVと比べて優れていた。テクスチャ解析から求めた指標は従来のものと比べ、悪性度評価において有用である可能性が示唆された。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2018/04 -2021/03 
    Author : Toyohara Jun
     
    In this study, we aimed to establish a method for non-invasive imaging of neurogenesis in the adult human brain. Therefore, we attempted to develop a tracer for positron emission tomography (PET) based on the same biochemistry as the currently established cell labeling method using bromo-deoxyuridine. The candidate compound 4DST showed accumulation in the subventricular zone and hippocampus with high cell proliferation activity, and autoradiographic analysis revealed that accumulation of 4DST in these sites was about twice that in the low cell proliferating cerebral cortex. In small animal PET study, we successfully imaged the subventricular zone, but the sensitivity was low. Attempts were made to develop a prodrug to improve the uptake of 4DST to the brain, but the target compound was not isolated within the research period.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2019/03 
    Author : ISHIWATA KIICHI; KUBO hitoshi; MIZUNO yasuaki; ISHII kenji; WAGATSUMA Kei
     
    We performed first clinical PET studies using 11C-preladenant (PLN) for imaging adenosine A2A receptor in the human brain. PLN-PET provided acceptable dosimetry and pharmacological safety. The PLN binding in brain regions was well correspond to the adenosine A2A receptor distribution in the brain. In drug-naive patients with Parkinson’s disease, the PLN binding did not changed in the striatum with age-matched healthy subjects, but bilateral difference in the head of caudate nucleus was slightly larger in the patients. In patients given the therapeutic doses of istradefylline occupancy rates of adenosine A2A receptors were about 70% at most in the striatum. These findings demonstrated that PLN-PET becomes a new tool for pathphysiological studies of neurodegenerative disease.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2019/03 
    Author : Yamamoto Yuka; MITAMURA Katsuya
     
    A novel radiopharmaceutical, C-11 4DST, has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. We evaluated C-11 4DST uptake on PET/CT in patients with newly diagnosed gliomas and correlated the results with proliferative activity and survival. Linear regression analysis indicated a significant correlation between MTV and Ki-67 index. The result of univariate analysis suggested that SUV was associated with OS. Mean survival for patients with SUV values less than 3.0 was longer, compared with those greater than 3.0. Based on the results of this preliminary study using C-11 4DST PET/CT, MTV seems to be useful for assessment of proliferation and SUV may be useful in the assessment of survival, in newly diagnosed gliomas.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2019/03 
    Author : Nishiyama Yoshihiro; MITAMURA Katsuya
     
    A new radiopharmaceutical, C-11 4DST, has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate the usefulness of C-11 4DST PET/CT for assessment of disease control of chemoradiotherapy for head and neck squamous cell carcinoma, in comparison with F-18 FDG PET/CT. Increased C-11 4DST and F-18 FDG uptake in primary lesion was visible. SUVafter values from C-11 4DST PET/CT in relapse-free group were significantly lower than those in relapse group. The percent change values from C-11 4DST PET/CT in relapse-free group were significantly higher than those in relapse group. Using F-18 FDG PET/CT, SUVafter and percent change were not significant differences between relapse-free and relapse groups.
  • 科学技術振興機構：産学が連携した研究開発成果の展開 研究成果展開事業 先端計測分析技術・機器開発プログラム 最先端研究基盤領域 機器開発タイプ
    Date (from‐to) : 2016 -2019 
    Author : 田中 浩士
     
    動物用PET装置を用いた動物体内でのリアルタイムの画像化が、化学物質の生体内挙動を得る簡便で有効な手段として注目されている。しかし、半減期の短い放射性PETプローブの供給において、その合成空間と時間の制約が、PETを用いた基礎研究の推進に大きな妨げとなっている。本課題では、精製用タグ法を利用する固相抽出精製法を採用することにより、HPLC装置を必要としない小型でシンプルな自動合成システムの開発を目指す。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2014/04 -2017/03 
    Author : FUKUMITSU Nobuyoshi; TOYOHARA Jun; THATANO Kentarou
     
    As a preclinical study of BNCT, we focused on collecting target data using X - rays. Cell viability of pancreatic cancer cells (BxPC-3) decreased dose-dependently. D10 was 1.28 Gy, and it was clarified that frequency of apoptosis is increased at the dose level. Expression analysis of cell death related protein by Western blotting method also increased the expression of Bax, but did not increase the expression of Bcl - 2, caspase 9, cleaved PARP. Similar results were obtained in animal experiments. In breast cancer cells (MDA-MB-231), the cell viability decreased in a dose-dependent manner, D10 was 3.92 Gy, and it was revealed that the dose increased frequency of apoptosis.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2014/04 -2017/03 
    Author : Ono Yuko
     
    4DST has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to investigate the feasibility of 4DST PET/CT for the detection of gastrointestinal cancer, in comparison with FDG PET/CT, and determined the degree of correlation between two radiotracers and proliferative activity as indicated by the Ki-67 index. Gastrointestinal cancer were detected by both 4DST and FDG PET/CT studies. A significant correlation was observed between 4DST SUV and FDG SUV. A significant correlation was observed between 4DST SUV and Ki-67 index and for FDG SUV. These preliminary results indicate that 4DST PET/CT seems to be useful in detecting gastrointestinal cancer and in the noninvasive assessment of proliferation, as similar as FDG PET/CT.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2017/03 
    Author : Toyohara Jun; ISHIWATA Kiichi; ISHII Kenji; ODA Keiichi; SAKATA Muneyuki; NARIAI Tadashi
     
    The thymidine derivative 11C-4DST has the potential to visualize in vivo DNA synthesis rates with positron emission tomography (PET). To expand the use of 4DST needs the fluorine-18 version of this compound. In this study, we tried to synthesize the 18F-4DST analogues for practical use of DNA synthesis imaging. The three candidates were selected. The fluoromethyl version of 4DST was not stable and cannot obtained as an purified form. The fluoroethyl version of 4DST can be labeled with using N3-Boc-3',5'-di-O-tolyl-5-tosyloxyethane precursor. However, biodistribution studies did not show tumor selective uptake. The 5-fluoro version of 4DST could be labeled by 18F anion with Cu-mediated nucleophilic fluorination of tin-precursor. However, the yields were very low. The acute toxicity studies indicate 5-fluoro-4DST is acceptable as PET drug for human use. In contrast, 5-fluror-4DST has mutagenic activity in E. Coli as indicated by the Ames study.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2016/03 
    Author : Yamamoto Yuka; KUDOMI Nobuyuki; KAWAI Nobuyuki; NISHIYAMA Yoshihiro; TOYOHARA Jun
     
    A novel radiopharmaceutical, 11C-4DST, has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate 11C-4DST uptake in patients with glioma and to correlate the results with proliferative activity and tumor grade, in comparison with 11C-Methionine and 18F-FLT. 11C-4DST is feasible for imaging of brain gliomas, as well as 11C-Methionine and 18F-FLT. Especially, it showed the highest correlation coefficient between 11C-4DST and Ki-67 index in newly diagnosed gliomas.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2012/04 -2016/03 
    Author : ISHIWATA Kiichi; MISHINA Masahiro; SAKATA Muneyuki; ISHIBASHI Kenji; ISHII Kenji; TOYOHARA Jun; ODA Keiichi; WAGATSUMA Kei; CHOU Meiei
     
    We performed first clinical PET studies using [11C]ITMM for imaging metablotropic glutamate receptor type 1 (mGluR1) in the human brain. [11C]ITMM-PET provided acceptable dosimetry and pharmacological safety. The [11C]ITMM binding in brain regions was well correspond to the mGluR1 distribution in the brain, suggesting that [11C]ITMM-PET becomes a new tool for pathphysiological studies of neurodegenerative disease. In healthy subjects [11C]ITMM binding increased in several brain regions of the elderly subjects. In patients with hereditary and sporadic cerebellar ataxia, the [11C]ITMM binding significantly decreased in cerebellar region compared with age-matched healthy subjects. The measurement of mGluR1 availability would be more sensitive than morphological measure by MRI. In Parkinson’s disease the binding decreased in cerebellum and temporal and parietal lobes. Preliminarily mGluR1 availability were regionally changed in the brain of patients with Alzheimer’s disease and epilepsy.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2011/04 -2015/03 
    Author : NARIAI Tadashi; TOYOHARA Jun; MATSUMURA Akira; TANAKA Yoji; TANAKA Yoji
     
    4’-[methyl-11C]thiotymidine（4DST) is a newly developed positron labelled pharmaceutical by our group incorporation of which into DNA compartment of in vivo tumor was confirmed for the first time. In the present clinical trial, we have undergone 86 scans of brain tumor or the suspects of brain tumor patients using 4DST together with 11C methionine, most widely used PET ligand for brain tumor in Japan, and compared the characteristics of 4DST imaging. Among all type of glioma, 4DST was confirmed to incorporate by reflecting proliferation rate of tumor cell more precisely than 11C methionine. 4DST was incorporated into malignant brain tumor infiltrating into the area with intact blood brain barrier. 4DST was revealed to be the most suitable PET probe to distinguish acute inflammation from malignant brain tumor. Further clinical trial is going on now.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2011 -2013 
    Author : TOYOHARA Jun; ISHIWATA Kiichi; SAKATA Muneyuki; ISHII Kenji; ODA Keiichi
     
    Five phenothiazine and a polyphenol derivatives were radiolabeled as potential PET molecular imaging probes for alpha-synuclein imaging in the brain. The four of five phenothiazine derivatives were successfully radiolabeled by 11C-methyl iodide or 11C-methyl triflate in a good yield with high specific activity. Dedicated small animal PET imaging showed these phenothiazine derivatives crossed the blood-brain barrier (BBB) with rapid washout from the brain. Another one-phenothiazine and polyphenol derivatives did not cross the BBB. In conclusion, our initial studies suggested that phenothiazine derivatives are good candidate for in vivo imaging of alpha-synuclein aggregation in the brain. Further structural optimizations of these compounds are needed.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010 -2012 
    Author : TOYOHARA Jun; KUBOTA Kazuo; YAMAMOTO Yuka; ISHIWATA Kiichi; ISHII Kenji; ODA Keiichi; SAKATA Muneyuki; NARIAI Tadashi; ELSINGA Philip; SCHWARTZ Jeffrey L.
     
    4DST is a newly developed PET tracer that can be used to image DNA synthesis, and its application in clinical settings is being studied at many facilities. 4DST will be applied to more types of cancer. Establishment of the clinical significance is needed.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2008 -2010 
    Author : ISHIWATA Kiichi; NARIAI Tadashi; MISHINA Masahiro; ISHII Kenji; ODA Keiichi; SAKATA Muneyuki; TOYOHARA Jun; KIMURA Yuichi
     
    To encourage PET pathophysiological studies and diagnosis of brain functions and brain disorders in Japan, practical and reliable database of many PET probes which evaluate the basic brain function such as blood flow and glucose metabolism and the neural transmission system was built. The database covers normal subjects including elderly and patients with brain disorders for several probes. Methodological improvement of PET measurement and data analysis with PET-MRI fusion was also performed.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2007 -2008 
    Author : TOYOHARA Jun
     
    チミジンホスホリラーゼの酵素活性を測定可能な放射性医薬品の開発を目的として,5'-デオキシ-5'-ヨードチミジン (1) および5'-デオキシ-5'-ヨードウリジン(2) をデザインし,その合成および評価を実施した。化合物 (1),(2) はともにチミジンホスホリラーゼによって,代謝を受けた。放射性ヨウ素で標識した (1) は,標的組織における放射能の滞留傾向と,他の臓器での放射能消失を認めた。一方,生体内での脱ヨウ素反応も認められた。

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