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[11C]TASP457, a novel PET ligand for histamine H3 receptors in human brain

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [11C]TASP0410457 ([11C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain.

Methods

Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [11C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme.

Results

[11C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 – 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm3 in the pallidum, 9 – 14 in the basal ganglia, 6 – 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [11C]TASP457 was 6.9 μSv/MBq.

Conclusion

[11C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.

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References

  1. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature. 1983;302:832–7.

    Article  CAS  PubMed  Google Scholar 

  2. Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci. 2003;4:121–30.

    Article  CAS  PubMed  Google Scholar 

  3. Goodchild RE, Court JA, Hobson I, Piggott MA, Perry RH, Ince P, et al. Distribution of histamine H3-receptor binding in the normal human basal ganglia: comparison with Huntington’s and Parkinson’s disease cases. Eur J Neurosci. 1999;11:449–56.

    Article  CAS  PubMed  Google Scholar 

  4. Esbenshade TA, Browman KE, Bitner RS, Strakhova M, Cowart MD, Brioni JD. The histamine H3 receptor: an attractive target for the treatment of cognitive disorders. Br J Pharmacol. 2008;154:1166–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ashworth S, Rabiner EA, Gunn RN, Plisson C, Wilson AA, Comley RA, et al. Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med. 2010;51:1021–9.

    Article  CAS  PubMed  Google Scholar 

  6. Ashworth S, Berges A, Rabiner EA, Wilson AA, Comley RA, Lai RYK, et al. Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET. Br J Pharmacol. 2014;171:1241–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jucaite A, Takano A, Boström E, Jostell K-G, Stenkrona P, Halldin C, et al. AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects. Int J Neuropsychopharmacol. 2013;16:1231–9.

    Article  CAS  PubMed  Google Scholar 

  8. Van Laere KJ, Sanabria-Bohórquez SM, Mozley DP, Burns DH, Hamill TG, Van Hecken A, et al. 11C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists. J Nucl Med. 2014;55:65–72.

    Article  PubMed  Google Scholar 

  9. Medhurst AD, Atkins AR, Beresford IJ, Brackenborough K, Briggs MA, Calver AR, et al. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer’s disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther. 2007;321:1032–45.

    Article  CAS  PubMed  Google Scholar 

  10. Koga K, Maeda J, Tokunaga M, Hanyu M, Kawamura K, Ohmichi M, et al. Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors. EJNMMI Res. 2016. doi:10.1186/s13550-016-0170-2.

  11. Wardak M, Wong KP, Shao W, Dahlbom M, Kepe V, Satyamurthy N, et al. Movement correction method for human brain PET images: application to quantitative analysis of dynamic 18F-FDDNP scans. J Nucl Med. 2010;51:210–8.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–9.

    Article  CAS  PubMed  Google Scholar 

  13. Akaike H. A new look at the statistical model identification. IEEE Trans Automat Contr. 1974;19:716–23.

    Article  Google Scholar 

  14. Fujita M, Seibyl JP, Verhoeff NP, Ichise M, Baldwin RM, Zoghbi SS, et al. Kinetic and equilibrium analyses of [123I]epidepride binding to striatal and extrastriatal dopamine D2 receptors. Synapse. 1999;34:290–304.

    Article  CAS  PubMed  Google Scholar 

  15. Hawkins RA, Phelps ME, Huang SC. Effects of temporal sampling, glucose metabolic rates, and disruptions of the blood–brain barrier on the FDG model with and without a vascular compartment: studies in human brain tumors with PET. J Cereb Blood Flow Metab. 1986;6:170–83.

    Article  CAS  PubMed  Google Scholar 

  16. Carson RE. Parameters estimation in positron emission tomography. In: Phelps ME, Mazziotta JC, Schelbert H, editors. Positron emission tomography and autoradiography: principle applications for the brain and the heart. New York: Raven Press; 1986. p. 347–90.

    Google Scholar 

  17. Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab. 1990;10:740–7.

    Article  CAS  PubMed  Google Scholar 

  18. Logan J, Fowler JS, Volkow ND, Ding Y-S, Wang G-J, Alexoff DL. A strategy for removing the bias in the graphical analysis method. J Cereb Blood Flow Metab. 2001;21:307–20.

    Article  CAS  PubMed  Google Scholar 

  19. Ichise M, Toyama H, Innis RB, Carson RE. Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab. 2002;22:1271–81.

    Article  PubMed  Google Scholar 

  20. Ichise M, Fujita M, Seibyl JP, Verhoeff NP, Baldwin RM, Zoghbi SS, et al. Graphical analysis and simplified quantification of striatal and extrastriatal dopamine D2 receptor binding with [123I]epidepride SPECT. J Nucl Med. 1999;40:1902–12.

    CAS  PubMed  Google Scholar 

  21. Kimura Y, Ito H, Shiraishi T, Fujiwara H, Kodaka F, Takano H, et al. Biodistribution and radiation dosimetry in humans of [11C]FLB 457, a positron emission tomography ligand for the extrastriatal dopamine D2 receptor. Nucl Med Biol. 2014;41:102–5.

    Article  CAS  PubMed  Google Scholar 

  22. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46:1023–7.

    PubMed  Google Scholar 

  23. Terry G, Liow J-S, Chernet E, Zoghbi SS, Phebus L, Felder CC, et al. Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents. Neuroimage. 2008;41:690–8.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hamill TG, Sato N, Jitsuoka M, Tokita S, Sanabria S, Eng W, et al. Inverse agonist histamine H3 receptor PET tracers labelled with carbon-11 or fluorine-18. Synapse. 2009;63:1122–32.

    Article  CAS  PubMed  Google Scholar 

  25. Zanotti-Fregonara P, Innis RB. Suggested pathway to assess radiation safety of 11C-labeled PET tracers for first-in-human studies. Eur J Nucl Med Mol Imaging. 2012;39:544–7.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank the radiology technologists of the PET Department and members of the Clinical Neuroimaging Team for their support with PET scans, Kazuko Suzuki and Shizuko Kawakami for their assistance as clinical coordinators, Hiromi Sano for her support with MRI scans, the staff of the Molecular Probe Program for radioligand synthesis and metabolite analysis, and Atsuo Waki and his team for quality assurance of the radioligand. The precursor and standard of [11C]TASP457 for this study were provided by Taisho Pharmaceutical Co., Ltd.

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Correspondence to Yasuyuki Kimura or Masanori Ichise.

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Funding

This study was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas (23111009, 26119531, 26118518) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, Health Labour Sciences Research Grant H25-Seishin-Jituyouka(Seishin)-Ippan-001 from the Ministry of Health, Labour and Welfare, Japan, and the Brain Mapping by Integrated Neurotechnologies for Disease Studies from the Japan Agency for Medical Research and Development.

Conflicts of interest

Y.K., K.T., S.K., M.H. and T.S. are involved in joint research and/or a clinical trial sponsored by Taisho Pharmaceutical Co., Ltd. M.H. and T.S. hold a patent for [11C]TASP457 and related chemicals as H3 ligands (Japan patent JP2014-47209A).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Kimura, Y., Seki, C., Ikoma, Y. et al. [11C]TASP457, a novel PET ligand for histamine H3 receptors in human brain. Eur J Nucl Med Mol Imaging 43, 1653–1663 (2016). https://doi.org/10.1007/s00259-016-3332-6

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  • DOI: https://doi.org/10.1007/s00259-016-3332-6

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