PET Radiopharmaceutical Sciences

Members

Theme Leader:
Jun Toyohara, Ph.D.
Researcher:
Muneyuki Sakata, Ph.D., Tetsuro Tago, Ph.D.
Adjunct Researcher:
Mikio Hiura, M.D., Ph.D., Yumi Yamamoto, Ph.D.

Keywords

Molecular imaging, PET tracer, First-in-human

Major Research Titles

  1. Development of novel PET tracers for clinical use
  2. Research on small animal imaging.

Profile

1. Development of novel PET tracers for clinical use
Our research objectives are the development of novel PET tracers, especially for neurodegenerative disorders and dementia, which develop frequently in elderly people. New PET tracers can provide new tools for the research and exploration of PET-based diagnosis of various diseases. For this purpose, we performed radio-synthesis of low molecular weight organic compounds with short half-lived positron emitters, basic biological evaluations of radiolabeled compounds, non-clinical studies of candidates, and first-in-human clinical trials. So far, eleven novel PET tracers have been developed. [11C]SA4503, [11C]MPDX, [11C]TMSX, O-[11C]methyl-L-tyrosine, [11C]CHIBA-1001, [11C]4DST, [11C]ITMM, [11C]CB184, [11C]Pleradenent, [18F]MC225 and [18F]FSW-100 were subjected to first-in-human clinical trials by us.
Furthermore, we continue the research by implementing various useful PET tracers developed by another institute and validate the image analysis method to cooperate with the clinical PET diagnosis.

2.Research on small animal imaging
We are studying physiological and pathological functions of small animals with PET tracer libraries with high performance preclinical total body PET/CT and 1T-bench top MRI, which will accelerate multimodal molecular imaging research in our institute.

References

Original Articles (Selected publication: first or corresponding author)

  1. Toyohara J, Sakata M, Wu J, Ishikawa M, Oda K, Ishii K, Iyo M, Hashimoto K, Ishiwata K. Preclinical and the first clinical studies on [11C]CHIBA-1001 for mapping a7 nicotinic receptors by positron emission tomography. Ann Nucl Med. 2009; 23:301-309.
  2. Toyohara J, Ishiwata K, Sakata M, Wu J, Nishiyama S, Tsukada H, Hashimoto K. In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys. PLoS One. 2010; 5:e8961.
  3. Sakata M, Wu J, Toyohara J, Oda K, Ishikawa M, Ishii K, Hashimoto K, Ishiwata K. Biodistribution and radiation dosimetry of the a7 nicotinic acetylcholine receptor ligand [11C]CHIBA-1001 in humans. Nucl Med Biol. 2011; 38:443-448.
  4. Toyohara J, Ishiwata K, Sakata M, Wu J, Nishiyama S, Tsukada H, Hashimoto K. In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys. Nucl Med Biol. 2011; 38:517-527.
  5. Toyohara J, Nariai T, Sakata M, Oda K, Ishii K, Kawabe T, Irie T, Saga T, Kubota K, Ishiwata K. Whole-Body Distribution and Brain Tumor Imaging with 11C-4DST: A Pilot Study. J Nucl Med. 2011; 52:1322-1328.
  6. Yamamoto Y, Toyohara J, Ishiwata K, Sano K, Yamamoto F, Mukai T, Maeda M. 11C-labeled analogs of indomethacin esters and amides for brain cyclooxygenase-2 imaging: radiosynthesis, in vitro evaluation and in vivo characteristics in mice. Chem Pharm Bull. 2011; 59:938-946.
  7. Toyohara J, Elsinga PH, Ishiwata K, Sijbesma JW, Dierckx RA, van Waarde A. Evaluation of 4¢-[methyl-11C]thiothymidine in a rodent tumor and inflammation model. J Nucl Med. 2012; 53:488-494.
  8. Toyohara J, Sakata M, Ishiwata K. Re-evaluation of in vivo selectivity of [11C]SA4503 to s1 receptors in the brain: contributions of emopamil binding protein. Nucl Med Biol. 2012; 39:1049-1052.
  9. Toyohara J, Kobayashi T, Mita S, Ishiwata K. Application of [¹¹C]SA4503 to selection of novel s₁ selective agonists. Nucl Med Biol. 2012; 39:1117-1121.
  10. Toyohara J, Sakata M, Oda K, Ishii K, Ishiwata K. Longitudinal observation of [11C]4DST uptake in turpentine-induced inflammatory tissue. Nucl Med Biol. 2013; 40:240-244.
  11. Toyohara J, Sakata M, Fujinaga M, Yamasaki T, Oda K, Ishii K, Zhang MR, Moriguchi Jeckel CM, Ishiwata K. Preclinical and the first clinical studies on [11C]ITMM for mapping metabotropic glutamate receptor subtype 1 by positron emission tomography. Nucl Med Biol. 2013; 40:214-220.
  12. Sakata M, Oda K, Toyohara J, Ishii K, Nariai T, Ishiwata K. Direct comparison of radiation dosimetry of six PET tracers using human whole-body imaging and murine biodistribution studies. Ann Nucl Med. 2013; 27:285-296.
  13. Toyohara J, Sakata M, Oda K, Ishii K, Ito K, Hiura M, Fujinaga M, Yamasaki T, Zhang MR, Ishiwata K. Initial human PET studies of metabotropic glutamate receptor type 1 ligand 11C-ITMM. J Nucl Med. 2013; 54:1302-1307.
  14. Hiura M, Nariai T, Ishii K, Sakata M, Oda K, Toyohara J, Ishiwata K. Changes in cerebral blood flow during steady-state cycling exercise: a study using oxygen-15-labeled water with PET. J Cereb Blood Flow Metab. 2014; 34:389-396.
  15. Okamoto M, Naka K, Kitagawa Y, Ishiwata K, Yoshimoto M, Shimizu I, Toyohara J. Synthesis and evaluation of 7a-(3-[18F]fluoropropyl) estradiol. Nucl Med Biol. 2015; 42:590-597.
  16. Toyohara J, Okamoto M, Aramaki H, Zaitsu Y, Shimizu I, Ishiwata K. (R)-[11C]emopamil as a novel tracer for imaging enhanced P-glycoprotein function. Nucl Med Biol. 2016; 43:52-62.
  17. Okamoto M, Shibayama H, Naka K, Kitagawa Y, Ishiwata K, Shimizu I, Toyohara J. Optimization of the alkyl side chain length of fluorine-18-labeled 7α-alkyl-fluoroestradiol. Nucl Med Biol. 2016; 43:512-519.
  18. Toyohara J, Sakata M, Hatano K, Yanai S, Endo S, Ishibashi K, Wagatsuma K, Ishii K, Ishiwata K. Preclinical and first-in-man studies of [11C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography. Ann Nucl Med. 2016; 30:534-543.
  19. Okamoto M, Naka K, Ishiwata K, Shimizu I, Toyohara J. Synthesis and basic evaluation of 7α-(3-[18F]fluoropropyl)-testosterone and 7α-(3-[18F]fluoropropyl)-dihydrotestosterone. Ann. Nucl. Med. 2017; 31:53-62.
  20. Hiura M, Sakata M, Ishii K, Toyohara J, Oda K, Nariai T, Ishiwata K. Central μ-opioidergic system activation evoked by heavy and severe-intensity cycling exercise in humans: a pilot study using positron emission tomography with 11C-carfentanil. Int J Sports Med. 2017; 38:19-26.
  21. Sakata M, Ishibashi K, Imai M, Wagatsuma K, Ishii K, Hatano K, Ishiwata K, Toyohara J. Assessment of safety, efficacy, and dosimetry of a novel 18-kDa translocator protein ligand, [11C]CB184, in healthy human volunteers. EJNMMI Res. 2017; 7:26.
  22. Sakata M, Toyohara J, Ishibashi K, Wagatsuma K, Ishii K, Zhang MR, Ishiwata K. Age and gender effects of 11C-ITMM binding to metabotropic glutamate receptor type 1 in healthy human participants. Neurobiol Aging 2017; 55:72-77.
  23. Sakata M, Ishibashi K, Imai M, Wagatsuma K, Ishii K, Zhou X, de Vries EF, Elsinga PH, Ishiwata K, Toyohara J. Initial evaluation of a novel adenosine A2A receptor ligand 11C-preladenant in healthy human subjects. J Nucl Med. 2017; 58:1464-1470.
  24. Hiura M, Nariai T, Sakata M, Muta A, Ishibashi K, Wagatsuma K, Tago T, Toyohara J, Ishii K, Maehara T. Response of cerebral blood flow and blood pressure to dynamic excerside: a study using PET. Int J Sports Med. 2018; 39:181-188.
  25. Hiura M, Nariai T, Takahashi K, Muta A, Sakata M, Ishibashi K, Toyohara J, Wagatsuma K, Tago T, Ishii K, Maehara T. Dynamic exercise elicits dissociated changes between tissue oxygenation and cerebral blood flow in the prefrontal cortex: a study using NIRS and PET. Adv Exp Med Biol. 2018; 1072:269-274.
  26. Tago T, Toyohara J, Harada R, Furumoto S, Okamura N, Kudo Y, Takahashi-Fujigasaki J, Murayama S, Ishii K. Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site. Ann Nucl Med. 2019; 33:375-382.
  27. Toyohara J, Yamamoto H, Tago T. Searching for diagnostic properties of nobel fluorine-18-labeled D-allose. Ann Nucl Med. 2019; 33:855-865.
  28. Tago T, Toyohara J, Ishii K. Radiosynthesis and preliminary evaluation of an 18F-labeled tubastatin A analog for PET imaging of histone deacetylase 6. J Labelled Comp Radiopharm. 2020; 63:85-95.
  29. Toyohara J, Sakata M, Tago T, Colabufo NA, Luurtsema G. Automated synthesis, preclinical toxicity, and radiation dosimetry of [18F]MC225 for clinical use: a tracer for P-glycoprotein function at the blood-brain barrier. EJNMMI Res. 2020; 10:84.
  30. Toyohara J, Harada N, Kakiuchi T, Ohba H, Kanazawa M, Tago T, Sakata M, Ishiwata K. Synthesis and evaluation of N-isopropyl-p-[11C]methylamphetamine as a novel cerebral blood flow tracer for positron emission tomography. EJNMMI Res. 2020; 10:115.
  31. Toyohara J, Nishino K, Sakai M, Tago T, Oda T. Automated production of [18F]MK-6240 on CFN-MPS200. Appl Radiat Isot. 2021; 168:109468.
  32. Tago T, Toyohara J, Fujimaki R, Tatsuta M, Ruichong S, Hirano K, Iwai K, Tanaka H. Effects of 18F-fluorinated glycol side-chain on the biological characteristics of stilbene amyloid-b PET ligands. Nucl Med Biol. 2021; 94-95:38-45.
  33. Tago T, Toyohara J, Ishii K. Preclinical evaluation of an 18F-labeled SW-100 derivative for PET imaging of histone deacetylase 6 in the brain. ACS Chem Neurosci. 2021; 12:746-755.
  34. Toyohara J, Sakata M, Ishibashi K, Mossel P, Imai K, Wagatsuma K, Tago T, Imabayashi E, Cola bufo NA, Luurtsema G, Ishii K. First clinical assessment of [18F]MC225, a novel fluorine-18 labelled PET tracer for measuring functionla P-glycoprotein at the blood-brain barrier. Ann Nucl Med. 2021; 35:1240-1252.
  35. Toyohara J, Sakata M, Wagatsuma K, Tago T, Ishibashi K, Ishii K. Test-retest reproducibility of cerebral adenosine A2A receptor quantification using [11C]preladenant. Ann Nucl Med. 2022; 36:15-23.
  36. Yamamoto Y, Tago T, Toyohara J, Saito Y, Yamamoto F. Radiosynthesis and in vivo and ex vivo evaluation of isomeric [11C]methoxy analogs of nimesulide as brain cyclooxygenase-2-targeted imaging agents. Biol Pharmacol Bull. 2022; 45:94-103.
  37. Tago T, Sakata M, Kanazawa M, Yamamoto S, Ishii K, Toyohara J. Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases. Eur J Nucl Med Mol Imaging. 2004; 51:2193-2203.
  38. Tago T, Toyohara J. Syep-by-step optimization of the radiosynthesis of the brain HDAC6 radioligand [18F]FSW-100 for clinical applications. EJNMMI Radiopharm Chem. 2024; 9:45.
  39. Toyohara J, Tago T, Sakata M. Process validation and preclinical development of a new PET cerebral blood flow tracer [11C]MMP for initial clinical trials. EJNMMI Radiopharm Chem. 2024; 29:53.
  40. Toyohara J, Komoda T, Tago T, Ito M, Yoshino H. Light up heart-type fatty acid binding protein (FABP3) with a novel fluorine-18 labelled selective FABP3 ligand. EJNMMI Res. 2024; 14:107.
  41. Tago T, Toyohara J. Carbon-11-labelling of the histone deacetylase 6 radioligand EKZ-001. Nucl Med Biol. 2025; 146-147:109030.
  42. Toyohara J, Ito M, Sakata M, Tago T, Komoda T, Yoshino H. Nonclinical investigations of a novel heart-type fatty acid-binding protein ligand, [18F]LUF: three-lot process validation, safety assessment, and radiation dosimetry. EJNMMI Radiopharm Chem. 2025; 10:72.

Reviews (Selected publication: first or corresponding author)

  1. Toyohara J, Sakata M, Ishiwata K. Imaging of sigma1 receptors in the human brain using PET and [11C]SA4503. CNS Agents Med Chem. 2009; 9:190-196.
  2. Toyohara J, Wu J, Hashimoto K. Recent development of radioligands for imaging of the a7 nicotinic acetylcholine receptors in the brain. Curr Top Med Chem. 2010; 10:1544-1557.
  3. Toyohara J, Hashimoto K. a7 Nicotinic receptor agonists: Potential therapeutic drugs for treatment of cognitive impairments in schizophrenia and Alzheimer's disease. Open Med Chem J. 2010; 4:37-56.
  4. Toyohara J, Ishiwata K. Animal tumor models for PET in drug development. Ann Nucl Med. 2011; 25:717-731.
  5. Toyohara J, Sakata M, Ishiwata K. Roles of s1 receptors in the mechanisms of action of CNS drugs. Trans Neurosci. 2012; 3:294-299.
  6. Toyohara J. Evaluation of DNA synthesis with carbon-11-labeled 4¢-thiothymidine. World J Radiol. 2016; 8:799-808.
  7. Toyohara J. Importance of P-gp PET imaging in pharmacology. Curr Pharm Des. 2016;22:5830-5836.
  8. Tago T, Toyohara J. Advances in the development of PET ligands targeting histone deacetylases fort he assessment of neurodegenerative diseases. Molecules 2018; 23:E300.
  9. Toyohara J. Development of PET radiopharmaceuticals at the Tokyo Metropolitan Institute of Gerontology 2010-2019. Ann Nucl Med Mol. 2020; 33:137-150.

Editorials (Selected publication: first or corresponding author)

  1. Toyohara J, Al-Qahtani M, Huang YY, Cazzola E, Todde S, Furumoto S, Mikolajczak R, Decristoforo C, Gillings N, Yang M, Reilly R, Duatti A, Denkova A, Schirrmacher R, Carlucci G, Seimbille Y, Liu Z, Ellis B, Cornelissen BT, Kopka K, Bernardes E. Highlight selection of radiochemistry and radiopharmacy developments by editorial board. EJNMMI Radiopharm Chem. 2022; 7:25.
  2. Toyohara J, Vugts D, Kiss OC, Todde S, Li XG, Liu Z, Yang Z, Gillings N, Cazzola E, Szymanski W, Meulen NX, Reilly R, Taddei C, Schirrmacher R, Li Z, Lagebo YJ, Bentaleb N, Souza Albernaz M, Lapi S, Ramogiada C, Mukherjee A, Ajenjo J, Deuther-Conard W, Boutdeau C. Highlight selection of radiochemistry and radiopharmacy developments by editorial board. EJNMMI Radiopharm Chem. 2024; 9:42.
  3. Toyohara J, Elsinga PH, Todde S, Li XG, Aime S, Szymanski WC, van der Meulen N, Cleeren F, Schirrmacher R, Yang H, Savio E, Bentaleb N, Zubillaga M, Chaple Gore IF, Bourgeois M, Mukherjee A, Pellico J, Kopka K. Highlight selection of radiochemistry and radiopjharmacy developed by editorial board. EJNMMI Radiopharm Chem. 2025; 10:65.

Case report (Selected publication: first or corresponding author)

  1. Tago T, Toyohara J, Sengoku R, Murayama S, Ishii K. MAO-B binding of 18F-THK5351 tp visualize glioblastoma and associated gliosis: an autopsy-confirmed case. Clin Nucl Med. 2019; 44:507-509.

Book Chapter

  1. Toyohara J, Ishiwata K: Animal models - Overview of animal models for tumors, brain diseases and genetics. In: Elsinga PH, van Waarde A, Paans AMJ, Dierckx RA, ed. Trends on the role of PET in drug development. World Scientific Publishing Co., 2012, pp.193-218.
  2. Toyohara J, Sakata M, Ishiwata K: Human brain imaging of acetylcholine receptors. In: Seeman P, Madras B, ed. Imaging of the human brain in health and disease. Academic Press, 2013, pp.99-112.
  3. Sakata M, Toyohara J, Ishiwata K: Brain imaging of sigma receptors. In: Seeman P, Madras B, ed. Imaging of the human brain in health and disease. Academic Press, 2013, pp.113-160
  4. Nariai T, Inaji M, Sakata M, Toyohara J. Use of 11C-4DST PET for imaging of human brain tumors. In: Hayat MA, ed. Tumors of the central nervous system. Volume 11. Springer Verlag, 2014, pp.41-48.
  5. Toyohara J, Sakata M, Ishiwata K: PET Imaging of Sigma-1 Receptors. In: Dierckx RA, Lutin PG, Otte A, de Vries E, van Waarde A, ed. PET and SPECT for Neurobiological systems. Springer Verlag, 2014, pp.744-758.
  6. Toyohara J, Brust P, Jia H, Sakata M, Ishiwata K: PET Imaging of Sigma1 Receptors. In: Dierckx RA, Otte A, de Vries EF, van Waarde A, Lammertsma AA, ed. PET and SPECT for Neurobiological Systems. Springer, Cham. 2021, pp.943-971.