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Characterization of the serotonin 2A receptor selective PET tracer (R)-[18F]MH.MZ in the human brain

  • Vasko KramerEmail author
  • Agnete Dyssegaard
  • Jonathan Flores
  • Cristian Soza-Ried
  • Frank Rösch
  • Gitte Moos Knudsen
  • Horacio Amaral
  • Matthias M. HerthEmail author
Original Article
Part of the following topical collections:
  1. Neurology

Abstract

Purpose

The serotonin receptor subtype 2A antagonist (5-HT2AR) (R)-[18F]MH.MZ has in preclinical studies been identified as a promising PET imaging agent for quantification of cerebral 5-HT2ARs. It displays a very similar selectivity profile as [11C]MDL 100907, one of the most selective compounds identified thus far for the 5-HT2AR. As [11C]MDL 100907, (R)-[18F]MH.MZ also displays slow brain kinetics in various animal models; however, the half-life of fluorine-18 allows for long scan times and consequently, a more precise determination of 5-HT2AR binding could still be feasible. In this study, we aimed to evaluate the potential of (R)-[18F]MH.MZ PET to image and quantify the 5-HT2AR in the human brain in vivo.

Methods

Nine healthy volunteers underwent (R)-[18F]MH.MZ PET at baseline and four out of these also received a second PET scan, after ketanserin pretreatment. Regional time–activity curves of 17 brain regions were analyzed before and after pretreatment. We also investigated radiometabolism, time-dependent stability of outcomes measures, specificity of (R)-[18F]MH.MZ 5-HT2AR binding, and performance of different kinetic modeling approaches.

Results

Highest uptake was determined in 5-HT2AR rich regions with a BPND of approximately 1.5 in cortex regions. No radiometabolism was observed. 1TCM and 2TCM resulted in similar outcome measure, whereas reference tissue models resulted in a small, but predictable bias. (R)-[18F]MH.MZ binding conformed to the known distribution of 5-HT2AR and could be blocked by pretreatment with ketanserin. Moreover, outcomes measures were stable after 100–110 min.

Conclusion

(R)-[18F]MH.MZ is a suitable PET tracer to image and quantify the 5-HT2AR system in humans. In comparison with [11C]MDL 100907, faster and more precise outcome measure could be obtained using (R)-[18F]MH.MZ. We believe that (R)-[18F]MH.MZ has the potential to become the antagonist radiotracer of choice to investigate the human 5-HT2AR system.

Keywords

[18F]MH.MZ MDL 100907 5-HT2A receptor Positron emission tomography (PET) Kinetic modeling 

Notes

Acknowledgments

The authors would like to thank Dr. Geoff Warnock from PMod Technologies, Switzerland, for his input regarding blood sampling and data evaluation as well as Dr. Evelyng Faure Lobos for acquiring the MRI scans at the Imaging Department of FALP (Instituto Oncológico Fundación Arturo López Pérez), Santiago de Chile, Chile. We also thank Carlos Elgueta and Dr. Mario Avila from Positronpharma for the assistance in tracer production and Irene Coudeu and Ana Hurtado for their help with technical issues.

Funding information

This study was in part funded by the Savværksejer Jeppe Juhls og Hustru Ovita Juhls foundation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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 (Comité Ético Cientifico, Servicio de Salud Metropolitano Oriente, permits 20150407 and 20170307) and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Supplementary material

259_2019_4527_MOESM1_ESM.docx (8.9 mb)
ESM 1 (DOCX 9153 kb)

References

  1. 1.
    Naughton M, Mulrooney JB, Leonard BE. A review of the role of serotonin receptors in psychiatric disorders. Hum Psychopharmacol Clin Exp. 2000;15(6):397–415.CrossRefGoogle Scholar
  2. 2.
    Nichols DE, Nichols CD. Serotonin receptors. Chem Rev. 2008;108(5):1614–41.CrossRefGoogle Scholar
  3. 3.
    Marazziti D. Understanding the role of serotonin in psychiatric diseases. F1000Res. 2017;6:180.CrossRefGoogle Scholar
  4. 4.
    Gonzalez-Maeso J, Sealfon SC. Psychedelics and schizophrenia. Trends Neurosci. 2009;32(4):225–32.CrossRefGoogle Scholar
  5. 5.
    Piel M, Vernaleken I, Rosch F. Positron emission tomography in CNS drug discovery and drug monitoring. J Med Chem. 2014;57(22):9232–58.CrossRefGoogle Scholar
  6. 6.
    Schrevens L, Lorent N, Dooms C, Vansteenkiste J. The role of PET scan in diagnosis, staging, and management of non-small cell lung cancer. Oncologist. 2004;9(6):633–43.CrossRefGoogle Scholar
  7. 7.
    Pennant M, Takwoingi Y, Pennant L, Davenport C, Fry-Smith A, Eisinga A, et al. A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence. Health Technol Assess. 2010;14(50):1–103.CrossRefGoogle Scholar
  8. 8.
    Kristensen JL, Herth MM. Textbook of drug design and discovery: in vivo imaging in drug discovery. Fifth edition ed 2017.Google Scholar
  9. 9.
    Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab. 2010;30(10):1682–706.CrossRefGoogle Scholar
  10. 10.
    Skinbjerg M, Sibley DR, Javitch JA, Abi-Dargham A. Imaging the high-affinity state of the dopamine D2 receptor in vivo: fact or fiction? Biochem Pharmacol. 2012;83(2):193–8.CrossRefGoogle Scholar
  11. 11.
    Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, et al. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. J Cereb Blood Flow Metab. 2014;34(7):1188–96.CrossRefGoogle Scholar
  12. 12.
    Herth MM, Knudsen GM. Current radiosynthesis strategies for 5-HT2A receptor PET tracers. J Label Compd Radiopharm. 2015;58(7):265–73.CrossRefGoogle Scholar
  13. 13.
    Grunder G, Yokoi F, Offord SJ, Ravert HT, Dannals RF, Salzmann JK, et al. Time course of 5-HT2A receptor occupancy in the human brain after a single oral dose of the putative antipsychotic drug MDL 100907 measured by positron emission tomography. Neuropsychopharmacology. 1997;17(3):175–85.CrossRefGoogle Scholar
  14. 14.
    Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM. 5-HT radioligands for human brain imaging with PET and SPECT. Med Res Rev. 2013;33(1):54–111.CrossRefGoogle Scholar
  15. 15.
    Madsen MK, Fisher PM, Burmester D, Dyssegaard A, Stenbaek DS, Kristiansen S, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. 2019.Google Scholar
  16. 16.
    Stenbaek DS, Kristiansen S, Burmester D, Madsen MK, Frokjaer VG, Knudsen GM, et al. Trait openness and serotonin 2A receptors in healthy volunteers: a positron emission tomography study. Hum Brain Mapp 2019.Google Scholar
  17. 17.
    Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, et al. Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther. 1996;277(2):968–81.PubMedGoogle Scholar
  18. 18.
    Herth MM, Kramer V, Piel M, Palner M, Riss PJ, Knudsen GM, et al. Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET. Bioorg Med Chem. 2009;17(8):2989–3002.CrossRefGoogle Scholar
  19. 19.
    Leysen JE. Use of 5-ht receptor agonists and antagonists for the characterization of their respective receptor sites. In: Boulton A, Baker G, Juorio A, editors. Drugs as tools in neurotransmitter research. Neuromethods. 12: Humana Press; 1989. p. 299–350.Google Scholar
  20. 20.
    Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P. Increased 5-HT2A receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [11C]MDL 100,907. Am J Psychiatry. 2006;163(9):1580–7.CrossRefGoogle Scholar
  21. 21.
    Hirani E, Sharp T, Sprakes M, Grasby P, Hume S. Fenfluramine evokes 5-HT2A receptor-mediated responses but does not displace [11C]MDL 100907: small animal PET and gene expression studies. Synapse. 2003;50(3):251–60.CrossRefGoogle Scholar
  22. 22.
    Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L. PET imaging of central 5-HT2A receptors with [11C]MDL 100907. J Nucl Med. 1998;39(1):208–14.PubMedGoogle Scholar
  23. 23.
    Watabe H, Channing MA, Der MG, Adams HR, Jagoda E, Herscovitch P, et al. Kinetic analysis of the 5-HT2A ligand [11C]MDL 100907. J Cereb Blood Flow Metab. 2000;20(6):899–909.CrossRefGoogle Scholar
  24. 24.
    Talvik-Lotfi M, Nyberg S, Nordstrom AL, Ito H, Halldin C, Brunner F, et al. High 5-HT2A receptor occupancy in MDL 100907 treated schizophrenic patients. Psychopharmacology. 2000;148(4):400–3.CrossRefGoogle Scholar
  25. 25.
    Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S, et al. Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab. 2003;23(8):985–96.CrossRefGoogle Scholar
  26. 26.
    Talbot PS, Slifstein M, Hwang DR, Huang Y, Scher E, Abi-Dargham A, et al. Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer [11C]MDL 100907 in humans: quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone. Neuroimage. 2012;59(1):271–85.CrossRefGoogle Scholar
  27. 27.
    Meyer PT, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM, Hinz R. Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100907 PET and non-invasive kinetic analyses. Neuroimage. 2010;50(3):984–93.CrossRefGoogle Scholar
  28. 28.
    Hinz R, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM. Validation of a tracer kinetic model for the quantification of 5-HT2A receptors in human brain with [11C]MDL 100907. J Cereb Blood Flow Metab. 2007;27(1):161–72.CrossRefGoogle Scholar
  29. 29.
    Hall H, Farde L, Halldin C, Lundkvist C, Sedvall G. Autoradiographic localization of 5-HT2A receptors in the human brain using [3H]MDL 100907 and [11C]MDL 100907. Synapse. 2000;38(4):421–31.CrossRefGoogle Scholar
  30. 30.
    Debus F, Herth MM, Piel M, Buchholz HG, Bausbacher N, Kramer V, et al. 18F-labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging. Nucl Med Biol. 2010;37(4):487–95.CrossRefGoogle Scholar
  31. 31.
    Hansen HD, Ettrup A, Herth MM, Dyssegaard A, Ratner C, Gillings N, et al. Direct comparison of [18F]MH.MZ and [18F]altanserin for 5-HT2A receptor imaging with PET. Synapse. 2013;67(6):328–37.CrossRefGoogle Scholar
  32. 32.
    Herth MM, Piel M, Debus F, Schmitt U, Luddens H, Rosch F. Preliminary in vivo and ex vivo evaluation of the 5-HT2A imaging probe [18F]MH.MZ. Nucl Med Biol. 2009;36(4):447–54.CrossRefGoogle Scholar
  33. 33.
    Herth MM, Debus F, Piel M, Palner M, Knudsen GM, Luddens H, et al. Total synthesis and evaluation of [18F]MH.MZ. Bioorg Med Chem Lett. 2008;18(4):1515–9.CrossRefGoogle Scholar
  34. 34.
    Herth MM, Kramer V, Gillings N, Rösch F, Knudsen GM. Direct radiofluorination of [18F]MH.MZ for 5-HT2A receptor molecular imaging with PET. J Label Compd Radiopharm. 2012;55(9):354–8.CrossRefGoogle Scholar
  35. 35.
    Abi-Dargham A, Martinez D, Mawlawi O, Simpson N, Hwang DR, Slifstein M, et al. Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility. J Cereb Blood Flow Metab. 2000;20(2):225–43.CrossRefGoogle Scholar
  36. 36.
    Gillings N. A restricted access material for rapid analysis of 11C-labeled radiopharmaceuticals and their metabolites in plasma. Nucl Med Biol. 2009;36(8):961–5.CrossRefGoogle Scholar
  37. 37.
    Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003;19(4):224–47.CrossRefGoogle Scholar
  38. 38.
    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(9):1533–9.CrossRefGoogle Scholar
  39. 39.
    Schmidt KC, Turkheimer FE. Kinetic modeling in positron emission tomography. Q J Nucl Med. 2002;46(1):70–85.PubMedGoogle Scholar
  40. 40.
    Pazos A, Cortes R, Palacios JM. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res. 1985;346(2):231–49.CrossRefGoogle Scholar
  41. 41.
    Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci U S A. 1997;94(10):5308–13.CrossRefGoogle Scholar
  42. 42.
    Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbol S, et al. A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: normative data and relationship to physiological and demographic variables. Neuroimage. 2004;21(3):1105–13.CrossRefGoogle Scholar
  43. 43.
    Horsager J, Munk OL, Sorensen M. Metabolic liver function measured in vivo by dynamic 18F-FDGal PET/CT without arterial blood sampling. EJNMMI Res. 2015;5:32–7.CrossRefGoogle Scholar
  44. 44.
    Sadzot B, Lemaire C, Maquet P, Salmon E, Plenevaux A, Degueldre C, et al. Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]altanserin: results in young normal controls. J Cereb Blood Flow Metab. 1995;15(5):787–97.CrossRefGoogle Scholar
  45. 45.
    Lundkvist C, Halldin C, Ginovart N, Nyberg S, Swahn CG, Carr AA, et al. [11C]MDL 100907, a radioligland for selective imaging of 5-HT2A receptors with positron emission tomography. Life Sci. 1996;58(10):PL 187–92.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Vasko Kramer
    • 1
    • 2
    Email author
  • Agnete Dyssegaard
    • 3
  • Jonathan Flores
    • 1
  • Cristian Soza-Ried
    • 1
  • Frank Rösch
    • 4
  • Gitte Moos Knudsen
    • 3
  • Horacio Amaral
    • 1
    • 2
  • Matthias M. Herth
    • 5
    • 6
    Email author
  1. 1.Center for Nuclear Medicine & PET/CT PositronmedSantiagoChile
  2. 2.Positronpharma SASantiagoChile
  3. 3.Center for Integrated Molecular Brain ImagingRigshospitalet and University of CopenhagenCopenhagenDenmark
  4. 4.Institute of Nuclear ChemistryJohannes Gutenberg-UniversityMainzGermany
  5. 5.Department of Drug Design and PharmacologyUniversity of CopenhagenCopenhagenDenmark
  6. 6.Department of Clinical Physiology, Nuclear Medicine & PETRigshospitaletCopenhagenDenmark

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