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Preclinical evaluation and test–retest studies of [18F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu5)

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

Abstract

Purpose

A novel, 18F-labelled metabotropic glutamate receptor subtype 5 (mGlu5) derivative of [11C]ABP688 ([11C]1), [18F]PSS232 ([18F] ]5), was evaluated in vitro and in vivo for its potential as a PET agent and was used in test–retest reliability studies

Methods

The radiosynthesis of [18F]5 was accomplished via a one-step reaction using a mesylate precursor. In vitro stability was determined in PBS and plasma, and with liver microsomal enzymes. Metabolite studies were performed using rat brain extracts, blood and urine. In vitro autoradiography was performed on horizontal slices of rat brain using 1 and 8, antagonists for mGlu5 and mGlu1, respectively. Small-animal PET, biodistribution, and test–retest studies were performed in Wistar rats. In vivo, dose-dependent displacement studies were performed using 6 and blocking studies with 7.

Results

[18F]5 was obtained in decay-corrected maximal radiochemical yield of 37 % with a specific activity of 80 – 400 GBq/μmol. Treatment with rat and human microsomal enzymes in vitro for 60 min resulted in 20 % and 4 % of hydrophilic radiometabolites, respectively. No hydrophilic decomposition products or radiometabolites were found in PBS or plasma. In vitro autoradiography on rat brain slices showed a heterogeneous distribution consistent with the known distribution of mGlu5 with high binding to hippocampal and cortical regions, and negligible radioactivity in the cerebellum. Similar distribution of radioactivity was found in PET images. Under displacement conditions with 6, reduced [18F]5 binding was found in all brain regions except the cerebellum. 7 reduced binding in the striatum by 84 % on average. Test–retest studies were reproducible with a variability ranging from 6.8 % to 8.2 %. An extended single-dose toxicity study in Wistar rats showed no compound-related adverse effects.

Conclusion

The new mGlu5 radiotracer, [18F]5, showed specific and selective in vitro and in vivo properties and is a promising radioligand for PET imaging of mGlu5 in humans.

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References

  1. DeLorenzo C, Kumar JSD, Mann JJ, Parsey RV. In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and 11C-ABP688. J Cereb Blood Flow Metab. 2011;31(11):2169–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A, et al. Reduced metabotropic glutamate receptor 5 density in major depression determined by 11C-ABP688 PET and postmortem study. Am J Psychiatry. 2011;168(7):727–34.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lüscher C, Huber KM. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron. 2010;65:445–59.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Ritzen A, Mathiesen JM, Thomsen C. Molecular pharmacology and therapeutic prospects of metabotropic glutamate receptor allosteric modulators. Basic Clin Pharmacol. 2005;97(4):202–13.

    Article  CAS  Google Scholar 

  5. Spooren W, Ballard T, Gasparini F, Amalric M, Mutel V, Schreiber R. Insight into the function of group I and group II metabotropic glutamate (mGlu) receptors: behavioral characterization and implications for the treatment of CNS disorders. Behav Pharmacol. 2003;14:257–77.

    Article  CAS  PubMed  Google Scholar 

  6. Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC. Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Mol Brain Res. 1998;56(1-2):207–17.

    Article  CAS  PubMed  Google Scholar 

  7. Pilc A, Klodzinska A, Branski P, Nowak G, Palucha A, Szewczyk B, et al. Multiple MPEP administrations evoke anxiolytic- and anti-depressant-like effects in rats. Neuropharmacology. 2002;43(2):181–7.

    Article  CAS  PubMed  Google Scholar 

  8. Cosford ND, Tehrani L, Roppe J, Schweiger E, Smith ND, Anderson J, et al. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem. 2003;46(2):204–6.

    Article  CAS  PubMed  Google Scholar 

  9. Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, et al. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGluR5 receptor antagonist. Neuropharmacology. 1999;38(10):1493–503.

    Article  CAS  PubMed  Google Scholar 

  10. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny CC, Tacconi S, et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci. 2001;4(9):873–4.

    Article  CAS  PubMed  Google Scholar 

  11. Todd PK, Mack KJ, Malter JS. The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Proc Natl Acad Sci U S A. 2003;100(24):14374–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Bruno V, Ksiazek I, Battaglia G, Lukic S, Leonhardt T, Sauer D, et al. Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective. Neuropharmacology. 2000;39(12):2223–30.

    Article  CAS  PubMed  Google Scholar 

  13. Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R. Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5 and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci. 2004;24(13):3370–8.

    Article  CAS  PubMed  Google Scholar 

  14. Ossowska K, Konieczny J, Wardas J, Pietraszek M, Kuter K, Wolfarth S, et al. An influence of ligands of metabotropic glutamate receptor subtypes on Parkinsonian-like symptoms and the striatopallidal pathway in rats. Amino Acids. 2007;32(2):179–88.

    Article  CAS  PubMed  Google Scholar 

  15. Rouse ST, Marino MJ, Bradley SR, Awad H, Wittmann M, Conn PJ. Distribution and roles of metabotropic glutamate receptors in the basal ganglia motor circuit: implications for treatment of Parkinson's disease and related disorders. Pharmacol Ther. 2000;88(3):427–35.

    Article  CAS  PubMed  Google Scholar 

  16. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 2003;6(1):43–50.

    Article  CAS  PubMed  Google Scholar 

  17. Aronica E, Catania MV, Geurts J, Yankaya B, Troost D. Immunohistochemical localization of group I and II metabotropic glutamate receptors in control and amyotropic lateral sclerosis human spinal cord: upregulation in reactive astrocytes. Neuroscience. 2001;105(2):509–20.

    Article  CAS  PubMed  Google Scholar 

  18. Aronica E, Gorter JA, Jansen GH, van Veelen CW, van Rijen PC, Ramkema M, et al. Expression and cell distribution of group I and II metabotropic glutamate receptor subtypes in Taylor-type focal cortical dysplasia. Epilepsia. 2003;44(6):785–95.

    Article  CAS  PubMed  Google Scholar 

  19. Ametamey SM, Kessler LJ, Honer M, Wyss MT, Buck A, Hintermann S, et al. Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J Nucl Med. 2006;47(4):698–705.

    CAS  PubMed  Google Scholar 

  20. Ametamey SM, Treyer V, Streffer J, Wyss MT, Schmidt M, Blagoev M, et al. Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. J Nucl Med. 2007;48(2):247–52.

    CAS  PubMed  Google Scholar 

  21. Burger C, Deschwanden A, Ametamey S, Johayem A, Mancosu B, Wyss M, et al. Evaluation of bolus/infusion protocol for 11C-ABP688, a PET tracer for mGluR5. Nucl Med Bio. 2010;37(7):845–51.

    Article  CAS  Google Scholar 

  22. Treyer V, Streffer J, Wyss MT, Bettio A, Ametamey SM, Fischer U, et al. Evaluation of the metabotropic glutamate receptor subtype 5 using PET and 11C-ABP688: assessment of methods. J Nucl Med. 2007;48(7):1207–15.

    Article  CAS  PubMed  Google Scholar 

  23. Wyss MT, Ametamey SM, Valerie T, Andrea B, Blagoev M, Kessler LJ, et al. Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and beta-scintillator. Neuroimage. 2007;35(3):1086–92.

    Article  PubMed  Google Scholar 

  24. Shetty HU, Zoghbi SS, Simeon FG, Liow JS, Brown AK, Kannan P, et al. Radiodefluorination of 3-fluoro-5-(2-(2-[18F](fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile ([18F]SP203), a radioligand for imaging brain metabotropic glutamate subtype-5 receptors with positron emission tomography, occurs by glutathionylation in rat brain. J Pharmacol Exp Ther. 2008;327(3):727–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Simeon FG, Brown AK, Zoghbi SS, Patterson VM, Innis RB, Pike VW. Synthesis and simple 18F-labeling of 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a high affinity radioligand for imaging monkey brain metabotropic glutamate subtype-5 receptors with positron emission tomography. J Med Chem. 2007;50(14):3256–66.

    Article  CAS  PubMed  Google Scholar 

  26. Barret O, Tamagnan G, Batis J, Jennings D, Zubal G, Russell D, et al. Quantitation of glutamate mGluR5 receptor with 18F-FPEB PET in humans. J Nucl Med. 2010;51 Suppl 2:215.

    Google Scholar 

  27. Wong DF, Waterhouse R, Kuwabara H, Kim J, Brasic JR, Chamroonrat W, et al. 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med. 2013;54(3):388–96.

    Article  CAS  PubMed  Google Scholar 

  28. Baumann CA, Mu L, Wertli N, Kramer SD, Honer M, Schubiger PA, et al. Syntheses and pharmacological charazterization of novel thiazole derivatives as potential mGluR5 PET ligands. Bioorg Med Chem. 2010;18(16):6044–54.

    Article  CAS  PubMed  Google Scholar 

  29. Honer M, Stoffel A, Kessler LJ, Schubiger PA, Ametamey SM. Radiolabeling and in vitro and in vivo evaluation of [18F]-FE-DABP688 as a PET radioligand for the metabotropic glutamate receptor subtype 5. Nucl Med Biol. 2007;34(8):973–80.

    Article  CAS  PubMed  Google Scholar 

  30. Lucatelli C, Honer M, Salazar JF, Ross TL, Schubiger PA, Ametamey SM. Synthesis, radiolabeling, in vitro and in vivo evaluation of [18F]-FPECMO as a positron emission tomography radioligand for imaging the metabotropic glutamate receptor subtype 5. Nucl Med Biol. 2009;36(6):613–22.

    Article  CAS  PubMed  Google Scholar 

  31. Sephton SM, Dennler P, Leutwiler D, Mu L, Wanger-Baumann CA, Schibli R, et al. Synthesis, radiolabelling and in vitro and in vivo evaluation of a novel fluorinated ABP688 derivative or the PET imaging of metabotropic glutamate receptor subtype 5. Am J Nucl Med Mol Imaging. 2012;2(1):14–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Sephton SM, Mu L, Schweizer WB, Schibli R, Krämer SD, Ametamey SM. Synthesis and evaluation of novel α-fluorinated (E)-3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyl oxime (ABP688) derivatives as metabotropic glutamate receptor subtype 5 PET radiotracers. J Med Chem. 2012;55(16):7154–62.

    Article  Google Scholar 

  33. Wanger-Baumann CA, Mu L, Honer M, Belli S, Alf MF, Schubiger PA, et al. In vitro and in vivo evaluation of [18F]-FDEGPECO as a PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5). Neuroimage. 2011;56(3):984–91.

    Article  CAS  PubMed  Google Scholar 

  34. Sephton SM, Mu L, Dragic M, Krämer SD, Schibli R, Ametamey SM. Synthesis and in vitro evaluation of E- and Z-geometrical isomers of PSS232 as potential metabotropic glutamate receptor subtype 5 (mGlu5) binders. Synthesis. 2013;45:1877–85.

    Article  CAS  Google Scholar 

  35. Lavreysen H, Wouters R, Bischoff F, Nobrega Pereira S, Langlois X, Blokland S, et al. JNJ16259685, a highly potent, selective and systemically active mGlu1 antagonist. Neuropharmacology. 2004;47(7):961–72.

    Article  CAS  PubMed  Google Scholar 

  36. Elmenhorst D, Aliaga A, Bauer A, Rosa-Neto P. Test-retest stability of cerebral mGluR5 quantification using [11C]ABP688 and positron emission tomography in rats. Synapse. 2012;66(6):552–60.

    Article  CAS  PubMed  Google Scholar 

  37. Yu M, Tueckmantel W, Wang X, Zhu A, Kozikowski AP, Brownell AL. Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine: synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors. Nucl Med Biol. 2005;32(6):631–40.

    Article  CAS  PubMed  Google Scholar 

  38. Anderson JJ, Bradbury MJ, Giracello DR, Chapman DF, Holtz G, Roppe J, et al. In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine). Eur J Pharmacol. 2003;473(1):35–40.

    Article  CAS  PubMed  Google Scholar 

  39. Kramer SD, Testa B. The biochemistry of drug metabolism – an introduction: Part 6. Inter-individual factors affecting drug metabolism. Chem Biodivers. 2008;5:2465–578.

    Article  CAS  PubMed  Google Scholar 

  40. Wang JQ, Tueckmantel W, Zhu A, Pellegrino D, Brownell AL. Synthesis and preliminary biological evaluation of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5. Synapse. 2007;61(12):951–61.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Aretussa Apladas and Martin Hungerbühler for technical support in the PET laboratory, Daniel Bieri, Dr. Lukas O. Dialer and Dr. Cindy R. Fischer for assistance with the biodistribution experiments, Stjepko Cermak (Institute Rudjer Boskovic, Zagreb, Croatia) for assistance with the test–retest study, and Susanne Geistlich for the toxicity studies. Dr. Thomas Nauser and Martina Dragic are acknowledged for support in the radiochemistry lab as well as Dominique Leutwiler with the microsome stability assays.

Conflicts of interest

None.

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Author notes

  1. Selena Milicevic Sephton

    Present address: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK

Authors and Affiliations

  1. Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland

    Selena Milicevic Sephton, Adrienne Müller Herde, Claudia Keller, Sonja Rüdisühli, Roger Schibli, Stefanie D. Krämer & Simon M. Ametamey

  2. Department of Nuclear Medicine, University Hospital Zürich, Rämistrasse 100, 8091, Zürich, Switzerland

    Linjing Mu

  3. Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland

    Yves Auberson

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  1. Selena Milicevic Sephton
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Correspondence to Simon M. Ametamey.

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Selena Milicevic Sephton and Adrienne Müller Herde contributed equally to this work.

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Sephton, S.M., Herde, A.M., Mu, L. et al. Preclinical evaluation and test–retest studies of [18F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu5). Eur J Nucl Med Mol Imaging 42, 128–137 (2015). https://doi.org/10.1007/s00259-014-2883-7

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  • DOI: https://doi.org/10.1007/s00259-014-2883-7

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