アイソトープ治療の副作用低減と治療効果増強を目的とした金属RI標識ペプチドの設計

• Project/Area Number: 15659277
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Radiation science
• Research Institution: Chiba University
• Principal Investigator: 荒野 泰 千葉大学, 大学院・薬学研究院, 教授 (90151167)
• Co-Investigator(Kenkyū-buntansha): 遠藤 啓吾 群馬大学, 医学部, 教授 (10115800) ; 上原 知也 千葉大学, 大学院・薬学研究院, 助手 (10323403)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥2,700,000 (Direct Cost: ¥2,700,000); Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: 放射性レニウム / テクネチウム-99m / 内用放射線治療 / 抗腫瘍抗体 / 抗腫瘍ペプチド / 腎障害 / ペプチド / 低分子化抗体 / テクネチウム / 腎集積 / 腎臓刷子縁膜酵素 / カルボキシペプチダーゼM / 代謝性スペーサ

Research Abstract

3'-[^<125>I]Iodohippuryl-N^ε-maleoyl-L-lysine (HML)は腎刷子縁膜酵素の作用でヨード馬尿酸を遊離し,RI標識ペプチドの腎臓での放射能滞留を投与早期から低減する.本成果を^<186>Reへ展開する目的で[^<186>Re]Cyclopentadienyltricarbonylrhenium carboxylic acid ([^<186>Re]CpTR-COOH)にN^ε-maleoyl-glycyl-lysineを結合した[^<186>Re]CpTR-GK(M)-OHを考案,合成した.本化合物のマレイミド基をBocに変換した誘導体は,ラット腎臓より調整した刷子縁膜小胞の作用で[^<186>Re]CpTR-Glyを遊離し,HMLと同様に刷子縁膜酵素により尿排泄性の化合物を遊離することを認めた.さらに,本化合物を用いて^<186>Re標識Fabを作製し,マウスに投与後の体内放射能動態を[^<186>Re]CpTR-COOHで作製した[^<186>Re]CpTR-Fabおよび[^<125>I]HML標識Fabと比較した.その結果,[^<186>Re]CpTR-Fabは投与30分後に腎臓への放射能集積が最大に達し,その後徐々に減少したのに対して,[^<186>Re]CpTR-GK(M)標識Fabは,[^<125>I]HML標識Fabと同様にインビボにおいても尿排泄性の放射性代謝物[^<186>Re]CpTR-Glyを遊離して、腎臓への集積を投与早期から大きく低減した.以上より,HMLの薬剤設計は,Reを始めとする金属RI標識ペプチドの腎集積の低減に有効であることを示す.

Research Products

• [Journal Article] Design of a radiopharmaceutical for the palliation of painful bone metastases : rhenium-186-labeled bisphosphonate derivative. (2004)
  • Author(s): K.Ogawa et al.
  • Journal Title: Journal of Labelled Compounds and Radiopharmaceuticals 47 Pages: 753-761
• [Journal Article] ^<99m>Tc-labeled mannosyl-neoglycoalbumin for sentinel lymph node identification. (2004)
  • Author(s): K.Takagi, et al.
  • Journal Title: Nuclear Medicine and Biology 31(7) Pages: 893-900
• [Journal Article] Conformational investigation of benzylhydroxamamide, its oxotechnetium(V) complexes (2004)
  • Author(s): K.Thipyapong, Y.Arano, V.Ruangpornvisuti.
  • Journal Title: Theochem 376(1-3) Pages: 65-71
• [Journal Article] A Tc-99m-Labeled Long Chain Fatty Acid Derivative for Myocardial Imaging. (2004)
  • Author(s): Y.Magata, et al.
  • Journal Title: Bioconjugate Chemistry 15(2) Pages: 389-393
• [Journal Article] Synthesis and evaluation of N-[^<18>F]fluoroethylpiperidin-4-ylmethyl acetate as a radiotracer for quantifying brain acetylcholinesterase activity by PET.
  • Author(s): T.Kikuchi, et al.
  • Journal Title: Journal of Medicinal Chemistry (in press)
• [Patent(Industrial Property Rights)] Somatostatin analogs and metal complex for MRI diagnosis and tratement of tumors. (2003)
  • Inventor(s): Saito Y., Saji H., Arano Y. et al.
  • Industrial Property Rights Holder: 日本メジフィジックス(株)
  • Filing Date: 2003-08-21
  • Acquisition Date: 2005-03-17
• [Patent(Industrial Property Rights)] Radioactive metal-cyclopentadieny carbonyl derivatives for disease diagnosis and treatment. (2003)
  • Inventor(s): Arano Y., Uehara T., et al.
  • Industrial Property Rights Holder: 日本メジフィジックス(株)
  • Filing Date: 2003-07-30
  • Acquisition Date: 2005-02-24
• [Patent(Industrial Property Rights)] Radioisotope-labeled monoclonal antibody specific for tenascine C for diagnosis of imflammation and tumor. (2003)
  • Inventor(s): Irie T., Tanada S., Hadokoro H., Arano Y., et al.
  • Industrial Property Rights Holder: JSTA, JNIRS
  • Filing Date: 2003-01-10
  • Acquisition Date: 2004-08-05
• [Publications] T.Uehara, M.Koike, H.Nakata, S.Miyamoto, S.Motoishi, K.Hashimoto, N.Oku, M.Nakayama, Y.Arano: "In vivo recognition of cyclopentadienyltricarbonylrhenium compounds."Nuclear Medicine and Biology. 30・3. 327-334 (2003)
• [Publications] T.Mukai, Y.Fujioka, Y.Arano, H.Saji: "Design of radiolabeled antibody fragments for tumor-selective radioactivity localization--brush border enzyme-sensitive bond to decrease renal accumulation of radioactivity."Yakugaku Zasshi. 123・8. 647-652 (2003)
• [Publications] R.Nisshii, K.Kawai, L.G.FloresII, H.Kataoka, S.Jinnouchi, S.Nagamachi, Y.Arano, S.Tamura: "A novel radiopharmaceutical for detection of malignant melanoma based on melanin formation : 3-iodo-4-hydroxyphenyl-L-cysteine."Nuclear Medicine Communication. 24・5. 575-582 (2003)
• [Publications] H.Akizawa, H.Takimoto, M.Saito, A.Iwado, M.Mifune, Y.Saito, T.Uehara, Y.Arano, T.Mukai, H.Hanaoka, H.Saji: "Effect of carbonylation of N-terminal phenylalanine of ^<111>In-DTPA-octreotide on radio-accumulation in kidney."Biological & Pharmaceutical Bulletin. 27・2. 271-272 (2004)
• [Publications] Y.Magata, T.Kawaguchi, M.Ukon, N.Yamamura, T.Uehara, K.Ogawa, Y.Arano, T.Temma, T.Mukai, E.Tadamura, H.Saji: "A Tc-99m-labeled long chain fatty acid derivative for myocardial imaging."Bioconjugate Chemistry. (in press).