[18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging

  • Laëtitia Lemoine
  • Mathieu Verdurand
  • Bernard Vacher
  • Elodie Blanc
  • Didier Le Bars
  • Adrian Newman-Tancredi
  • Luc Zimmer
Original Article

Abstract

Purpose

The serotonin-1A (5-HT1A) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT1A receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT1A receptors. Since all clinical PET 5-HT1A radiopharmaceuticals are antagonists, it is of great interest to develop a 18F labelled agonist.

Methods

F15599 (3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone) is a novel ligand with high affinity and selectivity for 5-HT1A receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT1A receptors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [18F]MPPF, a validated 5-HT1A antagonist radiopharmaceutical.

Results

The chemical and radiochemical purities of [18F]F15599 were >98%. In vitro [18F]F15599 binding was consistent with the known 5-HT1A receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [18F]F15599 binding, consistent with a specific binding to G protein-coupled receptors. In vitro binding of [18F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT1A antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain radioactive metabolites. Remarkably, in microPET studies, [18F]F15599 notably displayed a pattern of brain labelling that did not correlate with in vitro observations. Thus, in cat, the highest binding was observed in dorsal raphe and cingulate cortex with little binding in other cortical regions and none in hippocampus. In vivo binding was abolished by WAY100635, indicating specific labelling of 5-HT1A receptors.

Conclusion

[18F]F15599 is a radiofluorinated agonist presenting interesting characteristics for probing in vitro and in vivo the high-affinity states of the 5-HT1A receptors. Its differential labelling of 5-HT1A receptors in vitro and in vivo may result from its reported preferential interaction with receptors coupled to specific G-protein subtypes.

Keywords

Serotonin 1A receptor PET Agonist Rat Cat 

References

  1. 1.
    Fargin A, Raymond JR, Lohse MJ, Kobilka BK, Caron MG, Lefkowitz RJ. The genomic clone G-21 which resembles a beta-adrenergic receptor sequence encode the 5-HT1A receptor. Nature. 1988;335:358–60.CrossRefPubMedGoogle Scholar
  2. 2.
    Albert PR, Zhou QY, Van Tol HHM, Bunzow JR, Civelli O. Cloning functional expression, and mRN tissue distribution of the rat 5-hydroxytryptamine 1A receptor gene. J Biol Chem. 1990;265:5825–32.PubMedGoogle Scholar
  3. 3.
    Lanfumey L, Hamon M. 5-HT1 receptors. Curr Drug Targets CNS Neurol Dis. 2004;3:1–10.CrossRefGoogle Scholar
  4. 4.
    Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav. 2002;71:533–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Glennon RA. Serotonin receptors: clinical implications. Neurosci Biobehav Rev. 1990;14:35–47.CrossRefPubMedGoogle Scholar
  6. 6.
    Passchier J, van Waarde A. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. Eur J Nucl Med. 2001;28:113–29.CrossRefPubMedGoogle Scholar
  7. 7.
    Pike V, Halldin C, Wikström H. Radioligands for the study of brain 5-HT1A receptors in vivo. In: King FD, Oxford AW, editors. Progress in medicinal chemistry. Elsevier Science; 2001, p. 189–247.Google Scholar
  8. 8.
    Aznavour N, Zimmer L. [18F]MPPF as a tool for the in vivo imaging of 5-HT1A receptors in animal and human brain. Neuropharmacology. 2007;52:695–707.CrossRefPubMedGoogle Scholar
  9. 9.
    Kumar JS, Mann JJ. PET tracers for 5-HT(1A) receptors and uses thereof. Drug Discov Today. 2007;12:748–56.CrossRefPubMedGoogle Scholar
  10. 10.
    Emerit MB, el Mestikawy S, Gozlan H, Rouot B, Hamon M. Physical evidence of the coupling of solubilised 5-HT1A binding sites with G regulatory proteins. Biochem Pharmacol. 1990;39:7–18.CrossRefPubMedGoogle Scholar
  11. 11.
    Kobilka B. Adrenergic receptors as models for G protein-coupled receptors. Annu Rev Neurosci. 1992;15:87–114.CrossRefPubMedGoogle Scholar
  12. 12.
    Hall MD, El Mestikawy S, Emerit MB, Pichat L, Hamon M, Gozlan H. [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding to pre- and postsynaptic 5-Hydroxytryptamine sites in various regions of the rat brain. J Neurochem. 1985;44:1685–96.CrossRefPubMedGoogle Scholar
  13. 13.
    Mongeau R, Welner SA, Quirion R, Suranyi-Cadotte BE. Further evidence for differential affinity states of the serotonine 1A receptor in rat hippocampus. Brain Res. 1992;590:229–38.CrossRefPubMedGoogle Scholar
  14. 14.
    Nénonéné EK, Radja F, Carli M, Grondin L, Reader TA. Heterogeneity of cortical and hippocampal 5-HT1A receptors: a reappraisal of homogenate binding with 8-[3H]hydroxydipropylaminotetralin. J Neurochem. 1994;62:1822–34.PubMedCrossRefGoogle Scholar
  15. 15.
    Aznavour N, Rbah L, Léger L, et al. A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain. J Chem Neuroanat. 2006;31:226–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Maurel JL, Autin JM, Funes P, Newman-Tancredi A, Colpaert F, Vacher B. High efficacy 5-HT1A agonist for antidepressant treatment a renewed opportunity. J Med Chem. 2007;50:5024–33.CrossRefPubMedGoogle Scholar
  17. 17.
    Newman-Tancredi A, Martel JC, Assié MB, et al. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist. Br J Pharmacol. 2009;156:338–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Depoortere R, Auclair A, Bardin L, Newman-Tancredi A. F15599, a post-synaptic cortical preferential 5HT1A agonist: II) Effect in rodent models of cognitions and memory deficits. Eur Neuropsychopharmacol. 2008;18:S353.CrossRefGoogle Scholar
  19. 19.
    Llado-Pelfort L, Assie MB, Celada P, Newman-Tancredi A, Artigas F. F15599, a post-synaptic cortical preferential 5HT1A agonist: III) electrophysiology and microdialysis. Eur Neuropsychopharmacol. 2008;18:S246.CrossRefGoogle Scholar
  20. 20.
    Le Bars D, Bonmarchand G, Alvarez JM, Lemaire C, Mosdzianowski C. New automation of 18F-MPPF using a coincidence synthesizer. J Label Compd Radiopharm. 2001;44:S1045.CrossRefGoogle Scholar
  21. 21.
    Le Bars D, Lemaire C, Ginovart N, et al. High-yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY100635. Nucl Med Biol. 1998;25:343–50.CrossRefPubMedGoogle Scholar
  22. 22.
    Sempere-Roldan P, Chereul E, Dietzel O, et al. Raytest clearpet, a new generation small animal PET scanner. Nucl Instr Meth Phys Res A. 2007;571:498–501.CrossRefGoogle Scholar
  23. 23.
    Paxinos G, Watson C. The rat brain in stereotaxic coordinates. New York: Academic Press; 1986.Google Scholar
  24. 24.
    Jasper HH, Ajmone-Marsan C. A stereotaxic atlas of the diencephalon of the cat. Ottawa, Canada: The National Research Council of Canada editors; 1954.Google Scholar
  25. 25.
    Snyder RS, Niemer WT. A stereotaxic atlas of the cat brain. University of Chicago Press; 1961.Google Scholar
  26. 26.
    Schreiber G, Avissar S. Regulators of G-protein-coupled receptor-G-protein coupling: antidepressants mechanism of action. Expert Rev Neurother. 2007;7:75–84.CrossRefPubMedGoogle Scholar
  27. 27.
    Kegeles LS, Mann JJ. In vivo imaging of neurotransmitter systems using radiolabeled receptor ligands. Neuropsychopharmacology. 1997;17:293–307.CrossRefPubMedGoogle Scholar
  28. 28.
    Gozlan H, Ponchant M, Daval G, et al. 125I-Bolton-Hunter-8-methoxy-2-[N-propyl-N-propylamino]tetralin as a new selective radioligand of 5-HT1A sites in the rat brain. In vitro binding and autoradiographic studies. J Pharmacol Exp Ther. 1988;244:751–9.PubMedGoogle Scholar
  29. 29.
    Mathis CA, Huang Y, Simpson NR. Synthesis and evaluation of 5HT1A agonists as radioligands: failure of G protein-coupled receptor agonists as in vivo imaging agents. J Label Compd Radiopharm. 1997;40:563–4.Google Scholar
  30. 30.
    Suehiro M, Wang TS, Ytabe T, Van Heertum RL, Mann JJ. Syntheses of [11C] and [3H]LY274601, a serotonin 1A receptor agonist. J Label Compd Radiopharm. 1998;51:725–30. 51.CrossRefGoogle Scholar
  31. 31.
    Suehiro M, Underwood M, Arango V, et al. In vivo biodistribution of a radiotracer for imaging serotonin -1A receptor sites with PET: [11C]LY274601. Life Sci. 1998:1533–42.Google Scholar
  32. 32.
    Zimmer L, Fournet G, Benoît J, Guillaumet G, le Bars D. Carbon-11 labelling of 8[[3-[4-(2-[(11)C]methoxyphenyl)piperazin-1-yl]-2-hydroxypropyl]oxy]thiochroman, a presynaptic 5-HT(1A) receptor agonist, and its in vivo evaluation in anaesthetised rat and in awake cat. Nucl Med Biol. 2003;30:541–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Kumar JS, Majo VJ, Hsiung SC, et al. Synthesis and in vivo validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphtalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1, 2, 4]triazine-3, 5-dione: a novel 5-HT1A receptor agonist positron emission tomography ligand. J Med Chem. 2006;49:125–34.CrossRefPubMedGoogle Scholar
  34. 34.
    Kumar JSD, Prabhakaran J, Majo VJ, Milak MS, Hsiung S-C, Tamir H, et al. Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1, 2, 4-triazine-3, 5(2H, 4H)dione in nonhuman primates. Eur J Nucl Med Mol Imaging. 2007;34:1050–60.CrossRefPubMedGoogle Scholar
  35. 35.
    Newman-Tancredi A, Martel JC, Buritova J, Lauressergues E, Assie MB, Bruins Slot L, et al. F15599, a post-synaptic cortical preferential 5HT1A agonist: I) functionally-selective signal transduction profile. Eur Neuropsychopharmacol. 2008;18:S352.CrossRefGoogle Scholar
  36. 36.
    Laruelle M, Slifstein M, Huang Y. Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography. Mol Imaging Biol. 2003;5:363–75.CrossRefPubMedGoogle Scholar
  37. 37.
    la Cour Mannoury, El Mestikawy S, Hanoun N, Hamon M, Lanfumey L. Regional differences in the coupling of 5-Hydroxytryptamine-1A receptors to G proteins in the rat brain. Mol Pharmacol. 2006;70:1013–21.CrossRefGoogle Scholar
  38. 38.
    Zhuang ZP, Kung MP, Chumpradit S, Mu M, Kung HF. Derivatives of 4-(2′-methoxyphenyl)-1-[2′-(N-2"-pyridinyl-p-iodobenzamido)ethyl]pipera zine (p-MPPI) as 5-HT1A ligands. J Med Chem. 2004;37:4572–5.CrossRefGoogle Scholar
  39. 39.
    Assié MB, Cosi C, Koek W. Correlation between low/high affinities ratios for 5-HT1A receptors and intrinsic activity. Eur J Pharmacol. 1999;386:97–103.CrossRefPubMedGoogle Scholar
  40. 40.
    Patel S, Gibson R. In vivo site-directed radiotracer: a mini-review. Nucl Med Biol. 2008;35:805–15.CrossRefPubMedGoogle Scholar
  41. 41.
    Vacher B, Bonnaud B, Funes P, Jubault N, Koek W, Assié MB, et al. Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J Med Chem. 1999;42:1648–60.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Laëtitia Lemoine
    • 1
    • 2
  • Mathieu Verdurand
    • 1
    • 2
  • Bernard Vacher
    • 4
  • Elodie Blanc
    • 4
  • Didier Le Bars
    • 2
  • Adrian Newman-Tancredi
    • 4
  • Luc Zimmer
    • 1
    • 2
    • 3
  1. 1.Laboratory of NeuropharmacologyUniversité de LyonLyonFrance
  2. 2.PET DepartmentCERMEP – Imagerie du VivantLyonFrance
  3. 3.ANIMAGE DepartmentCERMEP – Imagerie du VivantLyonFrance
  4. 4.Centre de Recherches Pierre FabreCastresFrance

Personalised recommendations