A Versatile method for the synthesis of DTPA bearing functionalized side chain toward the application to MRI clinical diagnosis

• Project/Area Number: 22590101
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: The University of Tokushima
• Principal Investigator: NEMOTO Hisao 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (30208293)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: MRI / 重金属キレート / Stevens転位 / DTPA / 非侵襲診断 / グリシン / イミノ二酢酸 / EDTA

Research Abstract

A versatile method for the synthesis of DTPA bearing functionalized side chain was successfully accomplished. Introduction of only one side chain to DTPA, the key reaction, was succeeded in spite of the five reacting points in DTPA framework. Introduction of functional group at the terminus of the side chain, and connection of several pharmacokintic molecules with the functionalgroup was also succeeded. A parameter for MRI contrast of the target molecule was measured by MRI spectrometer. A compound was injected to mice to observe MRI image.

Research Products

• [Journal Article] Acute Oral Toxicity Evaluation of Symmetrically Branched Glycerol Trimer in ddY Mice (2012)
  • Author(s): Miyamoto, Licht; Watanabe, Masashi; Tomida, Yosuke; Kono, Mai; Fujii, Shoko; Matsushita, Tsuyoshi; Hattori, Hatsuhiko; Ishizawa, Keisuke; Nemoto, Hisao; Tsuchiya, Koichiro
  • Journal Title: J. Toxicol. Sci Volume: 37 Pages: 1253-1259
  • NAID: 10031126029
  • URL: http://dx.doi.org/10.2131/jts.37.1253
  • Peer Reviewed
• [Journal Article] Evaluation of the inhibitory effects of quercetin-related flavonoids and tea catechins on the monoamine oxidase-A reaction in mouse brain mitochondria (2012)
  • Author(s): Bandaruk, Yauhen; Mukai, Rie; Kawamura, Tomoyuki; Nemoto, Hisao; Terao, Junji
  • Journal Title: J. Agricul. Food Chem. Volume: 60 Pages: 10270-10277
  • URL: http://dx.doi.org/10.1021/jf303055b
  • Peer Reviewed
• [Journal Article] Prevention of Disuse Muscle Atrophy by Dietary Ingestion of 8-Prenylnaringenin in Denervation Mice (2012)
  • Author(s): Mukai, Rie; Horikawa, Hitomi; Fujikura, Yutaka; Kawamura, Tomoyuki; Nemoto, Hisao; Nikawa, Takeshi; Terao, Junji
  • Journal Title: PLoS One Volume: 4
  • NAID: 120006306635
  • Peer Reviewed
• [Journal Article] Synthesis of Paclitaxel-BGL Conjugates (2012)
  • Author(s): Nemoto, Hisao; Katagiri, Ayato; Kamiya, Masaki; Kawamura, Tomoyuki; Matsushita, Tsuyoshi; Matsumura, Kosuke; Itou, Tomohiro; Hattori, Hatsuhiko; Tamaki, Miho; Ishizawa, Keisuke; Miyamoto, Licht; Abe, Shinji; Tsuchiya, Koichiro
  • Journal Title: Bioorg. Med. Chem Volume: 20 Pages: 5559-5567
  • Peer Reviewed
• [Journal Article] Cytotoxicity Evaluation of Symmetrically Branched Glycerol Trimer in Human Hepatocellular Carcinoma HepG2 cells (2012)
  • Author(s): Miyamoto, Licht; Watanabe, Masashi; Kono, Mai; Matsushita, Tsuyoshi; Hattori, Hatsuhiko; Ishizawa, Keisuke; Nemoto, Hisao; Tsuchiya, Koichiro
  • Journal Title: J. Toxicol. Sci Volume: 37 Pages: 1059-1063
  • NAID: 10030876787
  • URL: http://dx.doi.org/10.2131/jts.37.1059
  • Peer Reviewed
• [Journal Article] Synthesis of Highly Water-soluble Fibrate Derivatives via BGLation (2012)
  • Author(s): Nemoto, Hisao; Kamiya, Masaki; Nakamoto, Aki; Matsushita, Tsuyoshi; Matsumura, Kosuke; Hattori, Hatsuhiko; Kawamura, Tomoyuki; Taoka, Chiaki; Abe, Shinji; Ishizawa, Keisuke; Miyamoto, Licht; Tsuchiya, Koichiro
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 22 Pages: 6425-6428
  • Peer Reviewed
• [Journal Article] Synthesis and Evaluation of Water-soluble Resveratrol and Piceatannol via BGLation (2012)
  • Author(s): Nemoto, Hisao; Katagiri, Ayato; Kamiya, Masaki; Matsushita, Tsuyoshi; Hattori, Hatsuhiko; Matsumura, Kosuke; Itou, Tomohiro; Kawamura, Tomoyuki; Kita, Toshiyuki; Nishida, Hana; Arakaki, Naokatu
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 22 Pages: 5051-5054
  • Peer Reviewed
• [Journal Article] An Efficient Method for the Refinement of 1,3-Methyleneglycerol via Bridged Acetal Exchange and Synthesis of the Symmetrically Branched Glycerol Trimer (2012)
  • Author(s): Hattori, Hatsuhiko; Matsushita, Tsuyoshi; Yoshitomi, Kohsuke; Katagiri, Ayato; Nemoto, Hisao
  • Journal Title: Synthesis 2012 Volume: 44 Pages: 2365-2373
  • Peer Reviewed
• [Journal Article] Frequency of C-allylations on oligoglycinates via N-ylides (2012)
  • Author(s): Nemoto, Hisao; Tamagawa, Shin-ya; Yatsuzuka, Kenji; Kawamura, Tomoyuki
  • Journal Title: J. Org. Chem Volume: 77 Pages: 4696-4705
  • URL: http://dx.doi.org/10.1021/jo300484x
  • Peer Reviewed
• [Journal Article] An Efficient Method for C8-Prenylation of Flavonols and Flavanones (2012)
  • Author(s): Kawamura, Tomoyuki; Hayashi, Moemi; Mukai, Rie; Terao, Junji; Nemoto, Hisao
  • Journal Title: Synthesis 2012 Volume: 44 Pages: 1308-1314
• [Journal Article] A Novel Liposome Surface Modification Agent that Prolongs Blood Circulation and Retains Surface Ligand Reactivity (2012)
  • Author(s): Ishihara, Atsushi; Yamauchi, Masahiro; Tsuchiya, Tomoko; Mimura, Yukiteru; Tomoda, Yutaka; Katagiri, Ayato; Kamiya, Masaki; Nemoto, Hisao; Suzawa, Toshiyuki; Yamasaki, Motoo
  • Journal Title: J. Biomaterials Sci., Polymer Ed Volume: 23 Pages: 2055-2068
  • Peer Reviewed
• [Journal Article] Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice (2012)
  • Author(s): Miyamoto, Licht et al (Miyamoto, Licht)
  • Journal Title: The Journal of Toxicological Sciences Volume: 37 Issue: 6 Pages: 1253-1259
  • DOI: 10.2131/jts.37.1253
  • NAID: 10031126029
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed
• [Journal Article] Synthesis of Paclitaxe-BGL Conjugates (2012)
  • Author(s): Nemoto, Hisao et al (Nemoto, Hisao)
  • Journal Title: Bioorg. Med. Chem. Volume: 20 Issue: 18 Pages: 5559-5567
  • DOI: 10.1016/j.bmc.2012.07.031
  • Peer Reviewed
• [Journal Article] Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells (2012)
  • Author(s): Miyamoto, Licht et al (Miyamoto, Licht)
  • Journal Title: The Journal of Toxicological Sciences Volume: 37 Issue: 5 Pages: 1059-1063
  • DOI: 10.2131/jts.37.1059
  • NAID: 130004446995
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed
• [Journal Article] Synthesis of Highly Water-soluble Fibrate Derivatives via BGLation (2012)
  • Author(s): Nemoto, Hisao et al (Nemoto, Hisao)
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Issue: 20 Pages: 6425-6428
  • DOI: 10.1016/j.bmcl.2012.08.057
  • Peer Reviewed
• [Journal Article] Synthesis and Evaluation of Water-soluble Resveratrol and Piceatannol via BGLation (2012)
  • Author(s): Nemoto, Hisao et al (Nemoto, Hisao)
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Issue: 15 Pages: 5051-5054
  • DOI: 10.1016/j.bmcl.2012.06.019
  • Peer Reviewed
• [Journal Article] An Efficient Method for the Refinement of 1,3-Methyleneglycerol via Bridged Acetal Exchange and Synthesis of the Symmetrically Branched Glycerol Trimer. (2012)
  • Author(s): Hattori, Hatsuhiko et al (Hattori, Hatsuhiko)
  • Journal Title: Synthesis Volume: 44 Issue: 15 Pages: 2365-2373
  • DOI: 10.1055/s-0031-1289809
  • Peer Reviewed
• [Journal Article] Frequency of C-allylations on oligoglycinates via N-ylides (2012)
  • Author(s): Nemoto, Hisao et al (Nemoto, Hisao)
  • Journal Title: J. Org. Chem. Volume: 77 Issue: 10 Pages: 4696-4705
  • DOI: 10.1021/jo300484x
  • Peer Reviewed
• [Journal Article] Improved performance by replacing iminodiacetic residues with glyceryl residues in symmetrically branched oligoglycerols (2011)
  • Author(s): Nemoto, Hisao; Ishihara, Atsushi; Araki, Takaaki; Katagiri, Ayato; Kamiya, Masaki; Matsushita, Tsuyoshi; Hattori, Hatsuhiko; Mimura, Yukiteru; Tomoda, Yutaka; Yamasaki, Motoo
  • Journal Title: performance by replacing iminodiacetic residues with glyceryl residues in symmetrically branched oligoglycerols Volume: 21 Pages: 4724-4727
  • Peer Reviewed
• [Journal Article] A highly selective mono-C-allylation of DTPA pentaethyl ester (2011)
  • Author(s): Nemoto, Hisao; Yatsuzuka, Kenji; Tamagawa, Shin-ya; Hirao, Naoko; Kamiya, Masaki; Kawamura, Tomoyuki
  • Journal Title: Synlett 2011 Pages: 615-618
  • Peer Reviewed
• [Journal Article] A Highly Selective Mono-C-allylation of DTPA Pentaethyl Ester (2011)
  • Author(s): Hisao Nemoto
  • Journal Title: Synlett Pages: 615-618
  • Peer Reviewed
• [Journal Article] An Efficient and Practical Method for the Preparation of a Branched Oligoglycerol with Acetonide Protection Groups (2010)
  • Author(s): Hisao Nemoto
  • Journal Title: Chemistry Letters Volume: 39 Pages: 856-857
  • NAID: 10027183882
  • Peer Reviewed
• [Journal Article] Preparation and properties of branched oligoglycerol modifiers for stabilization of liposomes (2010)
  • Author(s): Atsushi Ishihara
  • Journal Title: International Journal of Pharmaceutics Volume: 391 Pages: 237-243
  • Peer Reviewed
• [Presentation] 「有機合成技術による新しい MRI 用検査薬(造影剤)の開発」 放射線無用かつ切らずに挿さずに体内を視る (2012)
  • Author(s): 根本尚夫
  • Organizer: 鈴木章記念ケミストリーネックワーク設立講演会
  • Place of Presentation: 倉敷芸術科学大学(岡山県)
  • Year and Date: 2012-09-25
• [Presentation] BGL と XTPA の技術紹介 (2012)
  • Author(s): 根本尚夫
  • Organizer: JEREC 委託事業・目利き人材研修
  • Place of Presentation: 徳島大学常三島キャンパス(徳島県)
  • Year and Date: 2012-08-27
• [Presentation] 簡便大量合成技術を活かした独創型 MRI 造影剤の開発 A versatile and practical synthetic intermediate for MRI imaging agents (2012)
  • Author(s): 根本尚夫
  • Organizer: 第11 国際バイオテクノロジー展/技術会議 Biotech 2012
  • Place of Presentation: 東京ビッグサイト(東京都)
  • Year and Date: 2012-04-25
• [Presentation] 簡便大量合成技術を活かした独創型MRI造影剤の開発 (2012)
  • Author(s): 根本尚夫
  • Organizer: 第11国際バイオテクノロジー展/技術会議
  • Place of Presentation: 東京ビッグサイト(東京)
  • Invited
• [Presentation] BGLとXTPAの技術紹介 (2012)
  • Author(s): 根本尚夫
  • Organizer: JEREC委託事業・目利き人材研修
  • Place of Presentation: 徳島大学産学連携プラザ(徳島)
  • Invited
• [Presentation] 「有機合成技術による新しいMRI用検査薬(造影剤)の開発」 ～放射線無用かつ切らずに挿さずに体内を視る～ (2012)
  • Author(s): 根本尚夫
  • Organizer: 鈴木章記念ケミストリーネックワーク設立講演会
  • Place of Presentation: 倉敷芸術科学大学(倉敷)
  • Invited
• [Presentation] Synthesis of DTPA-Cholestanol Derivatives toward Potential MRI Contrast Medium (2011)
  • Author(s): Shin-ya Tamagawa, Kenji Yatsuzuka, Shinji Abe, Hitoshi Kubo, Koichiro Tsuchiya, Masafumi Harada, Hisao Nemoto
  • Organizer: the 8th AFMC International Medicinal Chemistry Symposium (AIMECS 11)
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2011-11-30
• [Presentation] Synthesis of DTPA-Cholestanol Derivatives toward Potential MRI Contrast Medium (2011)
  • Author(s): Shin-ya Tamagawa, Kenji Yatsuznka, Shinji Abe, Hitoshi Kubo, Koichiro Tsuchiya, Masafumi Harada, Hisao Nemoto
  • Organizer: the 8th AFMC. International Medicinal Chemistry Symposium (AIMECS 11)
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2011-11-30
• [Presentation] 新規 MRI造影剤の開発研究(The new development of MRI contrast medium) (2011)
  • Author(s): 玉川晋也・八塚研治・阿部真司・久保均・土屋浩一郎・原田雅史・根本尚夫
  • Organizer: 第37回反応と合成の進歩シンポジウム
  • Place of Presentation: あわぎんホール(徳島県郷土文化会館)(徳島県)
  • Year and Date: 2011-11-07
• [Presentation] 新規MRI造影剤の開発研究(The new development of MRI contrast medium) (2011)
  • Author(s): 玉川晋也・八塚研治・阿部真司・久保均・原田雅史・根本尚夫
  • Organizer: 第37回反応と合成の進歩シンポジウム
  • Place of Presentation: 徳島郷土文化会館(徳島)
  • Year and Date: 2011-11-07
• [Presentation] 構造ではなく性能を創る有機化学 (2011)
  • Author(s): 根本尚夫
  • Organizer: 東京工業大学大学院理工学研究科集中講義
  • Place of Presentation: 東京工業大学大岡山キャンパス(東京) (東京都)
  • Year and Date: 2011-05-27
• [Presentation] 薬を「溶かす」「視る」 水溶性化およびMRI造影剤創製に関する最近の成果ー (2011)
  • Author(s): 根本尚夫
  • Organizer: 東京工業大学大学院理工学研究科集中講義
  • Place of Presentation: 東京工業大学大岡山キャンパス(東京都)
  • Year and Date: 2011-05-27
• [Presentation] 薬を「溶かす」「視る」-水溶性化およびMR I造影剤創製に関する最近の成果- (2011)
  • Author(s): 根本尚夫
  • Organizer: 東京工業大学大学院理工学研究科集中講義
  • Place of Presentation: 東京工業大学(東京)(招待講演)
  • Year and Date: 2011-05-27
• [Presentation] 機能性 MRI 造影剤を指向したDTPA-cholestanol 誘導体の合成 (Design and synthesis of DTPA-cholestanol conjugations toward potential MRI contrast medium (2011)
  • Author(s): 玉川晋也・八塚研治・山崎豊・河村知志・根本尚夫
  • Organizer: 日本薬学会
  • Place of Presentation: ツインメッセ静岡 (静岡県)
  • Year and Date: 2011-03-31
• [Presentation] 機能性MRI造影剤を指向したDTPA-Cholestanol誘導体の合成 (2011)
  • Author(s): 玉川晋也・八塚研治・山崎豊・河村知志・根本尚夫
  • Organizer: 第234回日本薬学会年会
  • Place of Presentation: 静岡
  • Year and Date: 2011-03-30
• [Presentation] Kenji Yatsuzuka, Shin-ya Tmagawa, Tomoyuki Kawamura, Hisao Nemoto (2010)
  • Author(s): Kenji Yatsuzuka, Shin-ya Tmagawa, Tomoyuki Kawamura, Hisao Nemoto
  • Organizer: 2010 環太平洋国際化学会議
  • Place of Presentation: Hawaii Convention Hall (ハワイ州・米国)
  • Year and Date: 2010-12-19
• [Presentation] Highly selective mono-allylation of the compounds possessing multi-glycinate moieties (2010)
  • Author(s): Shin-ya Tmagawa, Kenji Yatsuzuka, Tomoyuki Kawamura, Hisao Nemoto
  • Organizer: 2010 環太平洋国際化学会議
  • Place of Presentation: Hawaii Convention Hall (ハワイ州・米国)
  • Year and Date: 2010-12-19
• [Presentation] Synthesis of C-Branched DTPA Derivatives toward MRI Contrast Medium (2010)
  • Author(s): Kenji Yatsuzuka, Shin-ya Tmagawa, Tomoyuki Kawamura, Hisao Nemoto
  • Organizer: 2010環太平洋国際化学会議
  • Place of Presentation: ホノルル(米国)
  • Year and Date: 2010-12-19
• [Presentation] Highly selective mono-allylation of the compounds possessing multi-glycinate moieties (2010)
  • Author(s): Shin-ya Tmagawa, Kenji Yatsuzuka, Tomoyuki Kawamura, Hisao Nemota
  • Organizer: 2010環太平洋国際化学会議
  • Place of Presentation: ホノルル(米国)
  • Year and Date: 2010-12-19
• [Presentation] 機能性 MRI 造影剤創製に向けた連結用官能基を有する DTPA 誘導体の合成 (2010)
  • Author(s): 八塚研治、玉川晋也、河村知志、根本尚夫
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都テレサ(京都府)
  • Year and Date: 2010-11-17
• [Presentation] 機能性MRI造影剤創製に向けた連結用官能基を有するDTPA誘導体の合成 (2010)
  • Author(s): 八塚研治、玉川晋也、河村知志、根本尚夫
  • Organizer: 第29回メデイシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-17
• [Presentation] 二段階型Stevens転位を用いた高選択的モノアリル化反応 (2010)
  • Author(s): 玉川晋也・八塚研治・河村知志・根本尚夫
  • Organizer: 第27回有機合成化学セミナー
  • Place of Presentation: 神戸
  • Year and Date: 2010-09-04
• [Remarks] 山陽新聞掲載:鈴木章記念ケミストリーネットワーク設立記念講演開催でMRI用造影剤の開発(講演者:根本 尚夫)を講演予定(XTPA) 2012年9月8日朝刊
• [Remarks] 山陽新聞掲載:第一線化学者が倉敷で講演「鈴木章ネット」設立記念2012年9月26日朝刊(辻二郎東工大栄誉教授・根本尚夫徳島大学准教授・山川富雄日本ケミファ投薬研究所所長による設立記念講演会)
  • URL: http://www.sanyo.oni.co.jp/news_s/news/d/2012092522413733/
• [Remarks] 1. 徳島大学薬学部機能分子合成薬学分野根本グループホームページ
  • URL: http://www.tokushima-u.ac.jp/ph/faculty/labo/nemoto/
• [Remarks] 2. Hisao Nemoto Project page-J
  • URL: http://dl.dropboxusercontent.com/u/49072831/index-J.html
• [Remarks] 3. Hisao Nemoto Publication List
  • URL: http://dl.dropboxusercontent.com/u/49072831/pub-E.html
• [Remarks] Hisao Nemoto Project page-E
  • URL: http://dl.dropboxusercontent.com/u/49072831/index.html
• [Remarks] 徳島大学薬学部機能分子合成薬学分野根本グループホームページ
  • URL: http://www.tokushima-u.ac.jp/ph/faculty/labo/nemoto/
• [Remarks] Hisao Nemoto Project page-J
  • URL: http://dl.dropboxusercontent.com/u/49072831/index-J.html
• [Remarks] Hisao Nemoto Publication List
  • URL: http://dl.dropboxusercontent.com/u/49072831/pub-E.html
• [Remarks] Hisao Nemoto Project page-E
  • URL: http://dl.dropboxusercontent.com/u/49072831/index.html
• [Remarks] この研究課題の基礎となった出願特許はH22年度にPCT拡張(JST支援)WO2011/074881となり、本H23年度に具体的な外国出願(欧米を中心とした4カ国)への移行(JST支援)が確定した。
• [Patent(Industrial Property Rights)] ジエチレントリアミン五酢酸誘導体の製造方法およびジエチレントリアミン五酢酸誘導体 (2010)
  • Inventor(s): 根本尚夫・河村知志・八塚研治・神谷昌樹
  • Industrial Property Rights Holder: 徳島大学
  • Filing Date: 2010-09-22
  • Overseas