Measurement of intracerebral drug concentration using magnetic resonance spectroscopy (MRS)

• Project/Area Number: 16H05385
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Radiation science
• Research Institution: Tohoku University
• Principal Investigator: TASHIRO Manabu 東北大学, サイクロトロン・ラジオアイソトープセンター, 教授 (00333477)
• Co-Investigator(Kenkyū-buntansha): 久保 均 福島県立医科大学, 新医療系学部設置準備室, 教授 (00325292) ; 伊藤 浩 福島県立医科大学, 医学部放射線科, 教授 (20360357) ; 渡部 浩司 東北大学, サイクロトロン・ラジオアイソトープセンター, 教授 (40280820) ; 佐々木 真理 岩手医科大学, 医歯薬総合研究所, 教授 (80205864)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 核磁気共鳴スペクトロスコピー（MRS) / ポジトロン放出断層法（PET) / 脳・神経 / 薬理学 / 脳内代謝物 / MRS / PET / 薬物動態 / 脳 / 薬物血中濃度 / 薬物脳内濃度 / 薬物代謝物濃度 / ポジトロン放出断層法（PET） / 受容体占拠率 / 脳内代謝物濃度

Outline of Final Research Achievements

In this project, non-invasive measurement of the intra-cerebral concentrations of orally-administered drugs (e.g. acetoaminophen or diphenhydramine) was tested in healthy humans using MR spectroscopy (MRS) function of PET/MR system. Results suggested it was not yet applicable to the measurement of other drugs although previous studies succeeded in measuring intra-cerebral ethanol concentration in humans. However, the results also demonstrated correlations between the plasma concentration change of the orally-administered drugs and intra-cerebral concentration of some selected brain metabolites. Based on this finding, it might be possible to estimate the intra-cerebral concentrations of orally-administered drugs in future.
In addition, additional PET measurement demonstrated an increased cerebral glucose consumption following oral administration of diphenhydramine especially during cognitive tasks. This finding might be useful to evaluate the effects of drugs on human brain activity.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ヒトが内服した薬物のうち脳内に分布した薬物分子に由来するMRS信号を体外計測して薬物の脳内濃度を推定することを目指したが、現在のMRS技術では困難であると示された。一方、服薬後の脳内代謝物由来のMRS信号を利用して内服薬物の脳内濃度を推定できる可能性があることが示唆され、将来、他の薬剤を用いた測定の実施が期待される。また、将来的にMRSの測定感度とデータ処理技術がさらに進歩した際には、ヒトの脳内薬物濃度を体外測定できる可能性があると期待される。
加えて、PETによる付随所見である薬物内服後の認知課題負荷時の脳代謝増加所見は、薬物による脳への影響を評価する指標としても有用と考えられた。

Research Products

• [Int'l Joint Research] Charite - Universitaetsmedizin Berlin(ドイツ)
• [Int'l Joint Research] Charite - Universitaetsmedizin Berlin(ドイツ)
• [Int'l Joint Research] Charite - Universitaetsmedizin Berlin(ドイツ)
• [Int'l Joint Research] Charite - Universitaetsmedizin Berlin(ドイツ)
• [Journal Article] Alzheimer's deterioration in intellectual and neurobiological staging supports the retrogenesis model: a double dissociation between verbal/non-verbal judgments and the left/right parieto-temporal glucose metabolism. A retrospective data analysis from the Tajiri Project. (2020)
  • Author(s): Meguro M, Meguro K, Takahashi K, Yamaguchi S, Tashiro M.
  • Journal Title: Psychogeriatrics. Volume: 20 Issue: 2 Pages: 149-155
  • DOI: 10.1111/psyg.12478
  • Peer Reviewed
• [Journal Article] A systematic performance evaluation of head motion correction techniques for 3 commercial PET scanners using a reproducible experimental acquisition protocol (2019)
  • Author(s): Takato Inomata,Shoichi Watanuki,Hayato Odagiri,Takeyuki Nambu,Nicolas A. Karakatsanis,Hiroshi Ito,Hiroshi Watabe,Manabu Tashiro,Miho Shidahara
  • Journal Title: Annals of Nuclear Medicine Volume: - Issue: 7 Pages: 459-470
  • DOI: 10.1007/s12149-019-01353-w
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Longitudinal changes in 18F-THK5351 PET in corticobasal syndrome (2019)
  • Author(s): Ezura M, Kikuchi A, Ishiki A, Okamura N, Hasegawa T, Harada R, Watanuki S, Funaki Y, Hiraoka K, Baba T, Sugeno N, Oshima R, Yoshida S, Kobayashi J, Kobayashi M, Tano O, Nakashima I, Mugikura S, Iwata R, Taki Y, Furukawa K, Arai H, Furumoto S, Tashiro M, Yanai K, Kudo Y, Takeda A, Aoki M
  • Journal Title: Eur J Neurol Volume: 26 Issue: 9 Pages: 1205-1211
  • DOI: 10.1111/ene.13966
  • Peer Reviewed / Open Access
• [Journal Article] Nuclear medicine practice in Japan: a report of the eighth nationwide survey in 2017. (2019)
  • Author(s): Nishiyama Y, Kinuya S, Kato T, Kayano D, Sato S, Tashiro M, Tatsumi M, Hashimoto T, Baba S, Hirata K, Yoshimura M, Yoneyama H.
  • Journal Title: Ann Nucl Med. Volume: 33 Issue: 10 Pages: 725-732
  • DOI: 10.1007/s12149-019-01382-5
  • Peer Reviewed
• [Journal Article] Brain histamine H1 receptor occupancy after oral administration of desloratadine and loratadine (2019)
  • Author(s): Nakamura Tadaho、Hiraoka Kotaro、Harada Ryuichi、Matsuzawa Takuro、Ishikawa Yoichi、Funaki Yoshihito、Yoshikawa Takeo、Tashiro Manabu、Yanai Kazuhiko、Okamura Nobuyuki
  • Journal Title: Pharmacology Research & Perspectives Volume: 7 Issue: 4
  • DOI: 10.1002/prp2.499
  • Peer Reviewed / Open Access
• [Journal Article] Error evaluation of the D-shuttle dosimeter technique in positron emission tomography study. (2019)
  • Author(s): Islam MS, Watanuki S, Tashiro M, Watabe H.
  • Journal Title: Radiol Phys Technol. Volume: 12 Issue: 4 Pages: 363-373
  • DOI: 10.1007/s12194-019-00530-w
  • Peer Reviewed
• [Journal Article] Renal statistical map for positron emission tomography with [O-15] water. (2019)
  • Author(s): Rahman M, Watabe H, Shidahara M, Watanuki S, Tashiro M, Mori T, Ito S, Ohsaki Y.
  • Journal Title: Am J Nucl Med Mol Imaging. Volume: 9 Pages: 193-202
  • Peer Reviewed
• [Journal Article] Investigation of the quantitative accuracy of low-dose amyloid and tau PET imaging. (2018)
  • Author(s): Nai YH, Watanuki S, Tashiro M, Okamura N, Watabe H.
  • Journal Title: Radiol Phys Technol. Volume: 11 Issue: 4 Pages: 451-459
  • DOI: 10.1007/s12194-018-0485-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Internal radiation dose estimation using multiple D-shuttle dosimeters for positron emission tomography (PET): A validation study using NEMA body phantom. (2018)
  • Author(s): Islam MS, Watanuki S, Tashiro M, Watabe H.
  • Journal Title: Med Phys. Volume: 45 Issue: 10 Pages: 4693-4703
  • DOI: 10.1002/mp.13124
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship between sympathoadrenal and pituitary-adrenal response during colorectal distention in the presence of corticotropin-releasing hormone in patients with irritable bowel syndrome and healthy controls. (2018)
  • Author(s): Tanaka Y, Kanazawa M, Kano M, Tashiro M, Fukudo S.
  • Journal Title: PLoS One Volume: 13 Issue: 7 Pages: 1-16
  • DOI: 10.1371/journal.pone.0199698
  • Peer Reviewed / Open Access
• [Journal Article] Neuroimaging-pathological correlations of [(18)F]THK5351 PET in progressive supranuclear palsy (2018)
  • Author(s): Ishiki A, Furukawa K, et al.
  • Journal Title: Acta Neuropathol Commun Volume: 6 Issue: 1 Pages: 53-53
  • DOI: 10.1186/s40478-018-0556-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Newly-Developed Positron Emission Mammography (PEM) Device for the Detection of Small Breast Cancer (2018)
  • Author(s): Yanai A, Itoh M, Hirakawa H, Yanai K, Tashiro M, Harada R, Yoshikawa A, Yamamoto S, Ohuchi N, Ishida T.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 245 Issue: 1 Pages: 13-19
  • DOI: 10.1620/tjem.245.13
  • NAID: 130006731329
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Effects of levocetirizine and diphenhydramine on regional glucose metabolic changes and hemodynamic responses in the human prefrontal cortex during cognitive tasks. (2018)
  • Author(s): Kikuchi A, Nasir FBM, Inami A, Mohsen A, Watanuki S, Miyake M, Takeda K, Koike D, Ito T, Sasakawa J, Matsuda R, Hiraoka K, Maurer M, Yanai1 K, Watabe H, Tashiro M.
  • Journal Title: Human Psychopharmacology. Volume: 33 Issue: 2
  • DOI: 10.1002/hup.2655
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlations of (18)F-THK5351 PET with Postmortem Burden of Tau and Astrogliosis in Alzheimer Disease. (2018)
  • Author(s): Harada R, Furukawa K, et al.
  • Journal Title: J Nucl Med Volume: 59 Issue: 4 Pages: 671-674
  • DOI: 10.2967/jnumed.117.197426
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A comparison of five partial volume correction methods for Tau and Amyloid PET imaging with [(18)F]THK5351 and [(11)C]PIB. (2018)
  • Author(s): Shidahara M, Thomas BA, Okamura N, Ibaraki M, Matsubara K, Oyama S, Ishikawa Y, Watanuki S, Iwata R, Furumoto S, Tashiro M, Yanai K, Gonda K, Watabe H.
  • Journal Title: Ann Nucl Med. Volume: 59 Issue: 7 Pages: 671-674
  • DOI: 10.1007/s12149-017-1185-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The clinical pharmacology of non-sedating antihistamines. (2017)
  • Author(s): Yanai K, Yoshikawa T, Yanai A, Nakamura T, Iida T, Leurs R, Tashiro M.
  • Journal Title: Pharmacol Ther. Volume: 178 Pages: 148-156
  • DOI: 10.1016/j.pharmthera.2017.04.004
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 抗ヒスタミン薬の鎮静作用と自動車運転における安全性：脳科学からの考察 (2020)
  • Author(s): 田代学
  • Organizer: 遠野市医師会学術講演会
  • Invited
• [Presentation] 抗ヒスタミン薬が認知課題遂行中のエネルギー消費に与える影響：FDG-PET研究. (2019)
  • Author(s): 田代 学、鈴木 頌也、Edmond CHEN、菊地 飛鳥 、稲見 暁惠、三宅 正泰、Fairuz Mohd NASIR、平岡 宏太良、四月朔日聖一、谷内 一彦、渡部 浩司.
  • Organizer: 第59回日本核医学会学術総会
• [Presentation] 脳画像医学で明らかにされる抗ヒスタミン薬の鎮静性副作用：ガンマ線および近赤外線を用いた脳イメージング技術の医学貢献. (2019)
  • Author(s): 田代学.
  • Organizer: 第41回日本光医学光生物学会
  • Invited
• [Presentation] Effects of antihistamines on regional glucose metabolic changes in human prefrontal cortex during cognitive tasks (2019)
  • Author(s): Nobuya Suzuki, Asuka Kikuchi, Akie Inami, Fairuz Binti Mohammadi Nasir, Attayeb Mohsen, Shoichi Watanuki, Masayasu Miyake, Kazuko Takeda, Kotaro Hiraoka, Kazuhiko Yanai, Hiroshi Watabe, Manabu Tashiro.
  • Organizer: NEURO2019（第42回日本神経科学大会）
• [Presentation] 一過性の運動による認知パフォーマンスの向上に対する内因性ドーパミンの関与. (2019)
  • Author(s): 安藤創一，藤本敏彦，四月朔日聖一，Fairuz Nasirナジールファイルーズ，平岡宏太良，武田和子，小林中，今野大成，リンユーチェンYuchen Lin，渡部浩司，田代学.
  • Organizer: 第74回体力医学会
• [Presentation] 抗ヒスタミン薬が認知課題遂行中の脳エネルギー消費に与える影響に関する脳PET研究 (2019)
  • Author(s): 鈴木頌也、菊地飛鳥、稲見暁惠、Attayeb Mohsen、松田林、平岡宏太良、四月朔日聖一、三宅正泰、渡部浩司、谷内一彦、田代学
  • Organizer: 第22回日本ヒスタミン学会
• [Presentation] Application of Nuclear Medicine to Brain research (2019)
  • Author(s): Tashiro M.
  • Organizer: Advanced Medical Imaging Physics: Egypt-Japan
  • Int'l Joint Research / Invited
• [Presentation] Status of Nuclear Medicine in Japan (2019)
  • Author(s): Tashiro M.
  • Organizer: Advanced Medical Imaging Physics: Egypt-Japan
  • Int'l Joint Research / Invited
• [Presentation] Functional Neuro-Imaging Research on Dementia (2019)
  • Author(s): Tashiro M.
  • Organizer: 17th Annual Meeting of Egyptian Society of Nuclear Medicine Specialists
  • Int'l Joint Research / Invited
• [Presentation] Evaluation of Double Injection Method for FDG PET Brain study (2018)
  • Author(s): Edmond Chen, Asuka Kikuchi, Akie Inami, Fairuz Binti Mohd Nasir, Attayeb Mohsen, Shoichi Watanuki, Masayasu Miyake, Kazuko Takeda, Kotaro Hiraoka, Kazuhiko Yanai, Hiroshi Watabe, Manabu Tashiro
  • Organizer: 日本ヒト脳機能イメージング研究会
• [Presentation] The recognition of small skeletal muscles: Pilot studies using PET/CT, PEM and PET/MR with 18F-FDG (2018)
  • Author(s): Yu-Chen Lin, Fumihiko Sato, Xudong Duan, Hitoshi Kubo, Taisei Konno, Katsuhiko Shibuya, Toshie Sugai, Ayaka Nemoto, Chieh-Hsiang Hsu, Soichi Ando, Hiroshi Itoh, Li-Chieh Kuo, Masatoshi Itoh, Manabu Tashiro
  • Organizer: 日本核医学会北日本地方会
• [Presentation] Effects of antihistamines on regional cerebral glucose metabolism and perfusion during cognitive tasks (2018)
  • Author(s): Asuka Kikuchi, Manabu Tashiro, Akie Inami, Fairuz Binti Mohammadi Nasir, Attayeb Mohsen, Shoichi Watanuki, Masayasu Miyake, Yuma Arakawa, Kazuko Takeda, Daigo Koike, Takayasu Ito, Junpei Sasakawa, Rin Matsuda, Kotaro Hiraoka, Kazuhiko Yanai, Hiroshi Watabe
  • Organizer: World Histamine Symposium
  • Int'l Joint Research
• [Presentation] 脳科学が語る抗ヒスタミン薬の鎮静性副作用 (2018)
  • Author(s): 田代学
  • Organizer: 柴田郡医師会学術講演会
  • Invited
• [Presentation] 脳科学が語る抗ヒスタミン薬の鎮静性副作用 (2018)
  • Author(s): 田代学
  • Organizer: TAIHO Web Lecture for Allergy
  • Invited
• [Presentation] Effects of antihistamines on regional cerebral glucose metabolism and perfusion during cognitive tasks. (2018)
  • Author(s): Kikuchi A, Tashiro M, Inami A, Fairuz BMN, Attayeb M, Watanuki S, Miyake S, Arakawa Y, Takeda K, Koike D, Ito T, Sasakawa J, Matsuda R, Hiraoka K, Yanai K, Watabe H.
  • Organizer: Asia Oceania Congress of Nuclear Medicine and Biology
  • Int'l Joint Research
• [Presentation] FDG-double-injection法による残留放射能補正の検討. (2018)
  • Author(s): 菊地飛鳥、田代学、渡部浩司、四月朔日聖一
  • Organizer: 第37回日本核医学技術学会学術総会
• [Presentation] レボセチリジンの鎮静作用に関する脳ブドウ糖代謝および脳血流の変化の観察 (2018)
  • Author(s): 田代学、菊地飛鳥、稲見暁惠、三宅正泰、Attayeb Mohsen、Fairuz Mohd Nasir、松田林、平岡宏太良、四月朔日聖一、谷内一彦、渡部浩司
  • Organizer: 第38回日本臨床薬理学会学術総会
• [Presentation] 脳科学が語る抗ヒスタミン薬の鎮静性副作用. (2017)
  • Author(s): 田代学
  • Organizer: 阪神アレルギーシンポジウム
  • Invited
• [Presentation] 脳科学が語る抗ヒスタミン薬の鎮静性副作用: 眠気とインペアードパフォーマンス (2017)
  • Author(s): 田代学
  • Organizer: Taiho Allergy Conference in Okinawa
  • Invited