Development of rapid C-methylation between two sp3-hybridized carbons for incorporation of short-lived positron-emitting 11C radionuclide

• Project/Area Number: 25460147
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Gifu University
• Principal Investigator: Koyama Hiroko 岐阜大学, 医学(系)研究科(研究院), 助教 (50402160)
• Co-Investigator(Kenkyū-buntansha): IJUIN Ryosuke 東京薬科大学, 薬学部, 助教 (40442925)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: PETプローブ合成 / アルキル－アルキル間クロスカップリング反応 / 高速反応 / ボロン化合物 / パラジウム触媒 / 鈴木・宮浦反応 / アルキル－アルキル間高速クロスカップリング反応 / 高速C-メチル化 / 高速C-[11C]メチル化 / 11C-標識法 / PET

Outline of Final Research Achievements

“Rapid C-[11C]methylation” is a groundbreaking methodology introduced for the synthesis of short-lived 11C-incorporated PET probes based on the use of C-C bond formation. The rapid cross-coupling reaction between two sp3-hybridized carbons remained to be explored. We developed Pd0-mediated cross couplings using CH3I (and [11C]CH3I) on the benzylic and allylic sp3 carbons applicable in various drug molecular structures. The utility of a rapid reaction was demonstrated by reacting between [11C]CH3I and boronic acid ester to afford N-(4-[11C]ethylphenyl)propionamide efficiently. The novel methodology possesses a high potential to incorporate the 11C radionuclide into organic frameworks in high reproducibility and high quality for human PET imaging.

Research Products

• [Journal Article] Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups. (2015)
  • Author(s): Soeda Y, Yoshikawa M, Almeida OF, Sumioka A, Maeda S, Osada H, Kondoh Y, Saito A, Miyasaka T, Kimura T, Suzuki M, Koyama H, Yoshiike Y, Sugimoto H, Ihara Y, Takashima A
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 10216-10216
  • DOI: 10.1038/ncomms10216
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficient syntheses of [11C]zidovudine and its analogues by convenient one-pot palladium(0)-copper(I)co-mediated rapid C-[11C]methylation. (2014)
  • Author(s): Zhouen Zhang, Hisashi Doi, Hiroko Koyama, Yasuyoshi Watanabe, Masaaki Suzuki
  • Journal Title: J. Label. Compd. Radiopharm. Volume: 57 Issue: 8 Pages: 540-549
  • DOI: 10.1002/jlcr.3213
  • Peer Reviewed
• [Journal Article] Synthesis of 11C-labeled retinoic acid, [11C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[11C]methylation (2014)
  • Author(s): Masaaki Suzuki, Misato Takashima-Hirano, Hideki Ishii, Chika Watanabe, Kengo Sumi, Hiroko Koyama, Hisashi Doi,
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 24 Issue: 15 Pages: 3622-3625
  • DOI: 10.1016/j.bmcl.2014.05.041
  • Peer Reviewed
• [Journal Article] Pd(0)-mediated rapid cross-coupling reactions, the rapid C-[11C]methylations, revolutionally advancing the syntheses of short-lived PET molecular probes (2014)
  • Author(s): Masaaki Suzuki, Hisashi Doi, Hiroko Koyama, Zhang Zhouen, Takamitsu Hosoya, Hirotaka Onoe, Yasuyoshi Watanabe
  • Journal Title: Chem. Rec. Volume: 14 Issue: 3 Pages: 516-541
  • DOI: 10.1002/tcr.201400002
  • Peer Reviewed
• [Journal Article] Synthesis of poly-substituted pyrazolo[1,5-a]quinolines through one-pot two component cascade reaction (2014)
  • Author(s): J. Kato, R. Ijuin, H. Aoyama, T. Yokomatsu
  • Journal Title: Tetrahedron Volume: 70 Issue: 17 Pages: 2766-2775
  • DOI: 10.1016/j.tet.2014.02.081
  • Peer Reviewed
• [Journal Article] Pd0-Mediated Rapid Coupling of Methyl Iodide with Excess Amounts of Benzyl- and Cinnamylboronic Acid Esters: Efficient Method for Incorporation of Positron–Emitting 11C Radionuclide into Organic Frameworks by Coupling between Two sp3-Hybridized Carbons (2013)
  • Author(s): Hiroko Koyama, Zhouen Zhang, Ryosuke Ijuin, Siqin, Jeongwan Son, Yuma Hatta, Masashi Ohta, Masahiro Wakao, Takamitsu Hosoya, Hisashi Doi, Masaaki Suzuki
  • Journal Title: RSC Advances Volume: 3 Issue: 24 Pages: 9391-9401
  • DOI: 10.1039/c3ra40815a
  • Peer Reviewed
• [Journal Article] Evaluation of TlOH Effect for Pd0-Mediated Cross-Coupling of Methyl Iodide and Excess Boronic Acid Ester toward Fabrication of [11C]CH3-Incorporated PET Tracer. (2013)
  • Author(s): Hiroko Koyama, Hisashi Doi, Masaaki Suzuki
  • Journal Title: Int. J. Org. Chem. Volume: 3 Issue: 03 Pages: 220-223
  • DOI: 10.4236/ijoc.2013.33030
  • Peer Reviewed
• [Journal Article] Novel Strategy for Synthesis of Substituted Benzimidazo[1,2-a]quinolines (2013)
  • Author(s): Jun-ya Kato, Yutaro Ito, Ryosuke Ijuin, Hiroshi Aoyama, Tsutomu Yokomatsu
  • Journal Title: Organic Letters Volume: 15 Issue: 14 Pages: 3794-3797
  • DOI: 10.1021/ol4017723
  • Peer Reviewed
• [Journal Article] Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats. (2013)
  • Author(s): Shingaki T, Takashima T, Ijuin R, Zhang X, Onoue T, Katayama Y, Okauchi T, Hayashinaka E, Cui Y, Wada Y, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y.
  • Journal Title: J Pharmacol Exp Ther Volume: 347 Issue: 1 Pages: 193-202
  • DOI: 10.1124/jpet.113.206425
  • Peer Reviewed
• [Presentation] Evaluation of TlOH Effects for Pd0-Mediated Cross-Coupling of Methyl Iodide and Excess Boronic Acid Esters toward 11C-Incorporated PET Tracer Synthesis (2015)
  • Author(s): Hiroko Koyama, Hisashi Doi, Masaaki Suzuki
  • Organizer: PACIFICHEM 2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] Synthesis of Disease Oriented and Novel PET Probe by Revolutionarily 11C Labeling Method (2015)
  • Author(s): Hiroko Koyama
  • Organizer: Japan-China Nuclear Medicine Joint Symposium in Okinawa
  • Place of Presentation: Mercure Hotel Okinawa, Naha
  • Year and Date: 2015-03-14 – 2015-03-15
  • Invited