Skip to main content

Advertisement

SpringerLink
Log in

Metabotropic glutamate receptor 5 – a promising target in drug development and neuroimaging

  • Review Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Balázs R, Bridges RJ, Cotman CW, ebrary Inc. Excitatory amino acid transmission in health and disease. In. Oxford University Press. 2005.

  2. van der Westhuizen ET, Valant C, Sexton PM, Christopoulos A. Endogenous allosteric modulators of G protein-coupled receptors. J Pharmacol Exp Ther. 2015;353:246–60.

    Article  PubMed  CAS  Google Scholar 

  3. Nickols HH, Conn PJ. Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol Dis. 2014;61:55–71.

    Article  PubMed  CAS  Google Scholar 

  4. Majo VJ, Prabhakaran J, Mann JJ, Kumar JS. PET and SPECT tracers for glutamate receptors. Drug Discov Today. 2013;18:173–84.

    Article  CAS  PubMed  Google Scholar 

  5. Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov. 2005;4:131–44.

    Article  CAS  PubMed  Google Scholar 

  6. Gereau RW, Swanson G, ebrary Inc. The glutamate receptors. In: The receptors. Humana Press. 2008.

  7. Corti C, Xuereb JH, Crepaldi L, Corsi M, Michielin F, Ferraguti F. Altered levels of glutamatergic receptors and Na+/K+ ATPase-alpha1 in the prefrontal cortex of subjects with schizophrenia. Schizophr Res. 2011;128:7–14.

    Article  PubMed  Google Scholar 

  8. Gupta DS, McCullumsmith RE, Beneyto M, Haroutunian V, Davis KL, Meador-Woodruff JH. Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Synapse. 2005;57:123–31.

    Article  CAS  PubMed  Google Scholar 

  9. Matosin N, Newell KA. Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia. Neurosci Biobehav Rev. 2013;37:256–68.

    Article  CAS  PubMed  Google Scholar 

  10. Matosin N, Fernandez-Enright F, Frank E, Deng C, Wong J, Huang XF, et al. Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics. J Psychiatry Neurosci : JPN. 2014;39:407–16.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ohnuma T, Tessler S, Arai H, Faull RL, McKenna PJ, Emson PC. Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus. Brain Res Mol Brain Res. 2000;85:24–31.

    Article  CAS  PubMed  Google Scholar 

  12. Richardson-Burns SM, Haroutunian V, Davis KL, Watson SJ, Meador-Woodruff JH. Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus. Biol Psychiatry. 2000;47:22–8.

    Article  CAS  PubMed  Google Scholar 

  13. Volk DW, Eggan SM, Lewis DA. Alterations in metabotropic glutamate receptor 1alpha and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. Am J Psychiatry. 2010;167:1489–98.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Fatemi SH, Folsom TD, Rooney RJ, Thuras PD. mRNA and protein expression for novel GABAA receptors theta and rho2 are altered in schizophrenia and mood disorders; relevance to FMRP-mGluR5 signaling pathway. Translational Psychiatry. 2013;3:e271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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. Brain Res Mol Brain Res. 1998;56:207–17.

    Article  CAS  PubMed  Google Scholar 

  16. Fatemi SH, Folsom TD. Dysregulation of fragile x mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study. Mol Autism. 2011;2:6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Fatemi SH, Folsom TD, Kneeland RE, Liesch SB. Metabotropic glutamate receptor 5 upregulation in children with autism is associated with underexpression of both Fragile X mental retardation protein and GABAA receptor beta 3 in adults with autism. Anat Rec (Hoboken, NJ : 2007). 2011;294:1635–45.

    Article  CAS  Google Scholar 

  18. 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;168:727–34.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kupila J, Karkkainen O, Laukkanen V, Tupala E, Tiihonen J, Storvik M. mGluR1/5 receptor densities in the brains of alcoholic subjects: a whole-hemisphere autoradiography study. Psychiatry Res. 2013;212:245–50.

    Article  CAS  PubMed  Google Scholar 

  20. Oka A, Takashima S. The up-regulation of metabotropic glutamate receptor 5 (mGluR5) in Down’s syndrome brains. Acta Neuropathol. 1999;97:275–8.

    Article  CAS  PubMed  Google Scholar 

  21. Iyer AM, van Scheppingen J, Milenkovic I, Anink JJ, Lim D, Genazzani AA, et al. Metabotropic glutamate receptor 5 in Down’s syndrome hippocampus during development: increased expression in astrocytes. Curr Alzheimer Res. 2014;11:694–705.

    Article  CAS  PubMed  Google Scholar 

  22. Pretto DI, Kumar M, Cao Z, Cunningham CL, Durbin-Johnson B, Qi L, et al. Reduced excitatory amino acid transporter 1 and metabotropic glutamate receptor 5 expression in the cerebellum of fragile X mental retardation gene 1 premutation carriers with fragile X-associated tremor/ataxia syndrome. Neurobiol Aging. 2014;35:1189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27:370–7.

    Article  CAS  PubMed  Google Scholar 

  24. Kandratavicius L, Rosa-Neto P, Monteiro MR, Guiot MC, Assirati Jr JA, Carlotti Jr CG, et al. Distinct increased metabotropic glutamate receptor type 5 (mGluR5) in temporal lobe epilepsy with and without hippocampal sclerosis. Hippocampus. 2013;23:1212–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Notenboom RG, Hampson DR, Jansen GH, van Rijen PC, van Veelen CW, van Nieuwenhuizen O, et al. Up-regulation of hippocampal metabotropic glutamate receptor 5 in temporal lobe epilepsy patients. Brain : J Neurol. 2006;129:96–107.

    Article  Google Scholar 

  26. Aronica E, Yankaya B, Jansen GH, Leenstra S, van Veelen CW, Gorter JA, et al. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol. 2001;27:223–37.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Boer K, Troost D, Timmermans W, Gorter JA, Spliet WG, Nellist M, et al. Cellular localization of metabotropic glutamate receptors in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Neuroscience. 2008;156:203–15.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Anneser JM, Chahli C, Ince PG, Borasio GD, Shaw PJ. Glial proliferation and metabotropic glutamate receptor expression in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2004;63:831–40.

    Article  CAS  PubMed  Google Scholar 

  31. Geurts JJ, Wolswijk G, Bo L, van der Valk P, Polman CH, Troost D, et al. Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Brain : J Neurol. 2003;126:1755–66.

    Article  CAS  Google Scholar 

  32. Dalfo E, Albasanz JL, Rodriguez A, Martin M, Ferrer I. Abnormal group I metabotropic glutamate receptor expression and signaling in the frontal cortex in Pick disease. J Neuropathol Exp Neurol. 2005;64:638–47.

    Article  CAS  PubMed  Google Scholar 

  33. Albasanz JL, Dalfo E, Ferrer I, Martin M. Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer’s disease and dementia with Lewy bodies correlates with stage of Alzheimer’s-disease-related changes. Neurobiol Dis. 2005;20:685–93.

    Article  CAS  PubMed  Google Scholar 

  34. Tsamis KI, Mytilinaios DG, Njau SN, Baloyannis SJ. Glutamate receptors in human caudate nucleus in normal aging and Alzheimer’s disease. Curr Alzheimer Res. 2013;10:469–75.

    Article  CAS  PubMed  Google Scholar 

  35. Gulyas B, Sovago J, Gomez-Mancilla B, Jia Z, Szigeti C, Gulya K, et al. Decrease of mGluR5 receptor density goes parallel with changes in enkephalin and substance P immunoreactivity in Huntington's disease: a preliminary investigation in the postmortem human brain. Brain Struct Funct. 2014.

  36. Ouattara B, Gregoire L, Morissette M, Gasparini F, Vranesic I, Bilbe G, et al. Metabotropic glutamate receptor type 5 in levodopa-induced motor complications. Neurobiol Aging. 2011;32:1286–95.

    Article  CAS  PubMed  Google Scholar 

  37. Lancaster E, Martinez-Hernandez E, Titulaer MJ, Boulos M, Weaver S, Antoine JC, et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology. 2011;77:1698–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stauffer SR. Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). ACS Chem Neurosci. 2011;2:450–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li G, Jorgensen M, Campbell BM. Metabotropic glutamate receptor 5-negative allosteric modulators for the treatment of psychiatric and neurological disorders (2009-July 2013). Pharm Pat Anal. 2013;2:767–802.

    Article  CAS  PubMed  Google Scholar 

  40. Sengmany K, Gregory KJ. Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias. Br J Pharmacol. 2015.

  41. Emmitte KA. mGlu5 negative allosteric modulators: a patent review (2010–2012). Expert Opin Ther Pat. 2013;23:393–408.

    Article  CAS  PubMed  Google Scholar 

  42. Kanuma K, Aoki T, Shimazaki Y. Recent patents on positive allosteric modulators of the metabotropic glutamate 5 receptor as a potential treatment for schizophrenia. Recent Pat CNS Drug Discov. 2010;5:23–34.

    Article  CAS  PubMed  Google Scholar 

  43. Bridges TM, Rook JM, Noetzel MJ, Morrison RD, Zhou Y, Gogliotti RD, et al. Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. Drug Metab Dispos. 2013;41:1703–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lindemann L, Porter RH, Scharf SH, Kuennecke B, Bruns A, von Kienlin M, et al. Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. J Pharmacol Exp Ther. 2015;353:213–33.

    Article  CAS  PubMed  Google Scholar 

  45. Scharf SH, Jaeschke G, Wettstein JG, Lindemann L. Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome. Curr Opin Pharmacol. 2015;20:124–34.

  46. Rascol O, Fox S, Gasparini F, Kenney C, Di Paolo T, Gomez-Mancilla B. Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias. Parkinsonism Relat Disord. 2014;20:947–56.

    Article  PubMed  Google Scholar 

  47. Sciamanna G, Ponterio G, Tassone A, Maltese M, Madeo G, Martella G, et al. Negative allosteric modulation of mGlu5 receptor rescues striatal D2 dopamine receptor dysfunction in rodent models of DYT1 dystonia. Neuropharmacology. 2014;85:440–50.

    Article  CAS  PubMed  Google Scholar 

  48. Stein MB, Steckler T, SpringerLink (Online service). Behavioral neurobiology of anxiety and its treatment. In: Current topics in behavioral neurosciences,. Springer-Verlag Berlin Heidelberg. 1999.

  49. Dominguez C, Burli RW, SpringerLink (Online service). Neurodegenerative diseases. In: Topics in medicinal chemistry,. Springer-Verlag Berlin Heidelberg. 1999.

  50. Marin JC, Goadsby PJ. Glutamatergic fine tuning with ADX-10059: a novel therapeutic approach for migraine? Expert Opin Investig Drugs. 2010;19:555–61.

    Article  CAS  PubMed  Google Scholar 

  51. Zerbib F, Bruley des Varannes S, Roman S, Tutuian R, Galmiche JP, Mion F, et al. Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2011;33:911–21.

    Article  CAS  PubMed  Google Scholar 

  52. Porter RH, Jaeschke G, Spooren W, Ballard TM, Buttelmann B, Kolczewski S, et al. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther. 2005;315:711–21.

    Article  CAS  PubMed  Google Scholar 

  53. Jacob W, Gravius A, Pietraszek M, Nagel J, Belozertseva I, Shekunova E, et al. The anxiolytic and analgesic properties of fenobam, a potent mGlu5 receptor antagonist, in relation to the impairment of learning. Neuropharmacology. 2009;57:97–108.

    Article  CAS  PubMed  Google Scholar 

  54. Raisz LG, Smith JA. Pathogenesis, prevention, and treatment of osteoporosis. Annu Rev Med. 1989;40:251–67.

    Article  CAS  PubMed  Google Scholar 

  55. Keck TM, Yang HJ, Bi GH, Huang Y, Zhang HY, Srivastava R, et al. Fenobam sulfate inhibits cocaine-taking and cocaine-seeking behavior in rats: implications for addiction treatment in humans. Psychopharmacology (Berl). 2013;229:253–65.

    Article  CAS  Google Scholar 

  56. Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med. 2012;4:131ra51.

    Article  PubMed  Google Scholar 

  57. Hughes ZA, Neal SJ, Smith DL, Sukoff Rizzo SJ, Pulicicchio CM, Lotarski S, et al. Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Neuropharmacology. 2013;66:202–14.

    Article  CAS  PubMed  Google Scholar 

  58. Reilmann R, Rouzade-Dominguez ML, Saft C, Sussmuth SD, Priller J, Rosser A, et al. A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington’s disease. Mov Disord. 2015;30:427–31.

    Article  CAS  PubMed  Google Scholar 

  59. Petrov D, Pedros I, de Lemos ML, Pallas M, Canudas AM, Lazarowski A, et al. Mavoglurant as a treatment for Parkinson’s disease. Expert Opin Investig Drugs. 2014;23:1165–79.

    Article  CAS  PubMed  Google Scholar 

  60. Movsesyan VA, O’Leary DM, Fan L, Bao W, Mullins PG, Knoblach SM, et al. mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors. J Pharmacol Exp Ther. 2001;296:41–7.

    CAS  PubMed  Google Scholar 

  61. Lea PM, Movsesyan VA, Faden AI. Neuroprotective activity of the mGluR5 antagonists MPEP and MTEP against acute excitotoxicity differs and does not reflect actions at mGluR5 receptors. Br J Pharmacol. 2005;145:527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li X, Need AB, Baez M, Witkin JM. Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther. 2006;319:254–9.

    Article  CAS  PubMed  Google Scholar 

  63. Klodzinska A, Tatarczynska E, Chojnacka-Wojcik E, Pilc A. Anxiolytic-like effects of group I metabotropic glutamate antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in rats. Pol J Pharmacol. 2000;52:463–6.

    CAS  PubMed  Google Scholar 

  64. Rasmussen K, Martin H, Berger JE, Seager MA. The mGlu5 receptor antagonists MPEP and MTEP attenuate behavioral signs of morphine withdrawal and morphine-withdrawal-induced activation of locus coeruleus neurons in rats. Neuropharmacology. 2005;48:173–80.

    Article  CAS  PubMed  Google Scholar 

  65. Paterson NE, Semenova S, Gasparini F, Markou A. The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology (Berl). 2003;167:257–64.

    CAS  Google Scholar 

  66. Paterson NE, Markou A. The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacology (Berl). 2005;179:255–61.

    Article  CAS  Google Scholar 

  67. van der Kam EL, de Vry J, Tzschentke TM. Effect of 2-methyl-6-(phenylethynyl) pyridine on intravenous self-administration of ketamine and heroin in the rat. Behav Pharmacol. 2007;18:717–24.

    Article  PubMed  CAS  Google Scholar 

  68. 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;46:204–6.

    Article  CAS  PubMed  Google Scholar 

  69. Lea PM, Faden AI. Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP. CNS Drug Rev. 2006;12:149–66.

    Article  CAS  PubMed  Google Scholar 

  70. Domin H, Zieba B, Golembiowska K, Kowalska M, Dziubina A, Smialowska M. Neuroprotective potential of mGluR5 antagonist MTEP: effects on kainate-induced excitotoxicity in the rat hippocampus. Pharmacol Rep. 2010;62:1051–61.

    Article  CAS  PubMed  Google Scholar 

  71. Varty GB, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, et al. The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles. Psychopharmacology (Berl). 2005;179:207–17.

    Article  CAS  Google Scholar 

  72. Stachowicz K, Golembiowska K, Sowa M, Nowak G, Chojnacka-Wojcik E, Pilc A. Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent. Neuropharmacology. 2007;53:741–8.

    Article  CAS  PubMed  Google Scholar 

  73. Adams CL, Cowen MS, Short JL, Lawrence AJ. Combined antagonism of glutamate mGlu5 and adenosine A2A receptors interact to regulate alcohol-seeking in rats. Int J Neuropsychopharmacol. 2008;11:229–41.

    Article  CAS  PubMed  Google Scholar 

  74. Palmatier MI, Liu X, Donny EC, Caggiula AR, Sved AF. Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine. Neuropsychopharmacology. 2008;33:2139–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gass JT, Osborne MP, Watson NL, Brown JL, Olive MF. mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats. Neuropsychopharmacology. 2009;34:820–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dravolina OA, Danysz W, Bespalov AY. Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats. Psychopharmacology (Berl). 2006;187:397–404.

    Article  CAS  Google Scholar 

  77. Rohof WO, Lei A, Hirsch DP, Ny L, Astrand M, Hansen MB, et al. The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers. Aliment Pharmacol Ther. 2012;35:1231–42.

    Article  CAS  PubMed  Google Scholar 

  78. Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ, et al. Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther. 2003;306:116–23.

    Article  CAS  PubMed  Google Scholar 

  79. Balschun D, Zuschratter W, Wetzel W. Allosteric enhancement of metabotropic glutamate receptor 5 function promotes spatial memory. Neuroscience. 2006;142:691–702.

    Article  CAS  PubMed  Google Scholar 

  80. Moghaddam B. Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl). 2004;174:39–44.

    Article  CAS  Google Scholar 

  81. Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, et al. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1- yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. J Pharmacol Exp Ther. 2008;327:827–39.

    Article  CAS  PubMed  Google Scholar 

  82. Engers DW, Rodriguez AL, Williams R, Hammond AS, Venable D, Oluwatola O, et al. Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273. ChemMedChem. 2009;4:505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Schlumberger C, Pietraszek M, Gravius A, Klein KU, Greco S, More L, et al. Comparison of the mGlu(5) receptor positive allosteric modulator ADX47273 and the mGlu(2/3) receptor agonist LY354740 in tests for antipsychotic-like activity. Eur J Pharmacol. 2009;623:73–83.

    Article  CAS  PubMed  Google Scholar 

  84. Kinney GG, O’Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, et al. A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther. 2005;313:199–206.

    Article  CAS  PubMed  Google Scholar 

  85. Cleva RM, Hicks MP, Gass JT, Wischerath KC, Plasters ET, Widholm JJ, et al. mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration. Behav Neurosci. 2011;125:10–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Horio M, Fujita Y, Hashimoto K. Therapeutic effects of metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on phencyclidine-induced cognitive deficits in mice. Fundam Clin Pharmacol. 2013;27:483–8.

    Article  CAS  PubMed  Google Scholar 

  87. Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JS, McNaughton CH, et al. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology. 2009;57:531–8.

    Article  CAS  PubMed  Google Scholar 

  88. Doria JG, de Souza JM, Andrade JN, Rodrigues HA, Guimaraes IM, Carvalho TG, et al. The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington’s disease. Neurobiol Dis. 2015;73:163–73.

    Article  CAS  PubMed  Google Scholar 

  89. Zhao Z, Wisnoski DD, O’Brien JA, Lemaire W, Williams Jr DL, Jacobson MA, et al. Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA. Bioorg Med Chem Lett. 2007;17:1386–91.

    Article  CAS  PubMed  Google Scholar 

  90. O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, et al. A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J Pharmacol Exp Ther. 2004;309:568–77.

    Article  PubMed  CAS  Google Scholar 

  91. Conde-Ceide S, Martinez-Viturro CM, Alcazar J, Garcia-Barrantes PM, Lavreysen H, Mackie C, et al. Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia. ACS Med Chem Lett. 2015;6:716–20.

    Article  CAS  PubMed  Google Scholar 

  92. Gilmour G, Broad LM, Wafford KA, Britton T, Colvin EM, Fivush A, et al. In vitro characterisation of the novel positive allosteric modulators of the mGlu(5) receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat. Neuropharmacology. 2013;64:224–39.

    Article  CAS  PubMed  Google Scholar 

  93. Gastambide F, Cotel MC, Gilmour G, O’Neill MJ, Robbins TW, Tricklebank MD. Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator. Neuropsychopharmacology. 2012;37:1057–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gastambide F, Gilmour G, Robbins TW, Tricklebank MD. The mGlu(5) positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat. Neuropharmacology. 2013;64:240–7.

    Article  CAS  PubMed  Google Scholar 

  95. Zhang ZY, Sun BL, Liu JK, Yang MF, Li DW, Fang J, et al. Activation of mGluR5 Attenuates Microglial Activation and Neuronal Apoptosis in Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats. Neurochem Res. 2015;40:1121–32.

    Article  CAS  PubMed  Google Scholar 

  96. Rodriguez AL, Grier MD, Jones CK, Herman EJ, Kane AS, Smith RL, et al. Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol. 2010;78:1105–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. D’Amore V, Santolini I, van Rijn CM, Biagioni F, Molinaro G, Prete A, et al. Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats. Neuropharmacology. 2013;66:330–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. D’Amore V, Santolini I, Celli R, Lionetto L, De Fusco A, Simmaco M, et al. Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats. Neuropharmacology. 2014;85:91–103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Hamill TG, Krause S, Ryan C, Bonnefous C, Govek S, Seiders TJ, et al. Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers. Synapse. 2005;56:205–16.

    Article  CAS  PubMed  Google Scholar 

  100. Patel S, Hamill TG, Connolly B, Jagoda E, Li W, Gibson RE. Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F]FPEB. Nucl Med Biol. 2007;34:1009–17.

    Article  CAS  PubMed  Google Scholar 

  101. Hae Kang J, Lee M, Hoon Ryu Y, Hyoung Lyoo C, Hoon Kim C, Chul Lee K, et al. [18F]FPEB and [18F]FDEGPECO comparative study of mGlu5 quantification in rodent brain. Appl Radiat Isot. 2015;98:103–7.

    Article  CAS  Google Scholar 

  102. Rook JM, Tantawy MN, Ansari MS, Felts AS, Stauffer SR, Emmitte KA, et al. Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles. Neuropsychopharmacology. 2015;40:755–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kil KE, Zhu A, Zhang Z, Choi JK, Kura S, Gong C, et al. Development of [123I]IPEB and [123I]IMPEB as SPECT Radioligands for Metabotropic Glutamate Receptor Subtype 5. ACS Med Chem Lett. 2014;5:652–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Belanger MJ, Krause SM, Ryan C, Sanabria-Bohorquez S, Li W, Hamill TG, et al. Biodistribution and radiation dosimetry of [18F]FPEB in nonhuman primates. Nucl Med Commun. 2008;29:915–9.

    Article  PubMed  Google Scholar 

  105. Kessler RM, Seibyl J, Cowan RL, Zald D, Young JS, Ansari MS, et al. Radiation Dosimetry of [18F]FPEB in Humans. J Nucl Med. 2014;55:1119–21.

    Article  PubMed  Google Scholar 

  106. 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;54:388–96.

    Article  CAS  PubMed  Google Scholar 

  107. 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;327:727–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Brown AK, Kimura Y, Zoghbi SS, Simeon FG, Liow JS, Kreisl WC, et al. Metabotropic glutamate subtype 5 receptors are quantified in the human brain with a novel radioligand for PET. J Nucl Med. 2008;49:2042–8.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kimura Y, Simeon FG, Hatazawa J, Mozley PD, Pike VW, Innis RB, et al. Biodistribution and radiation dosimetry of a positron emission tomographic ligand, [18F]SP203, to image metabotropic glutamate subtype 5 receptors in humans. Eur J Nucl Med Mol Imaging. 2010;37:1943–9.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Simeon FG, Liow JS, Zhang Y, Hong J, Gladding RL, Zoghbi SS, et al. Synthesis and characterization in monkey of [11C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors. Eur J Nucl Med Mol Imaging. 2012;39:1949–58.

    Article  CAS  PubMed  Google Scholar 

  111. 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;47:698–705.

    CAS  PubMed  Google Scholar 

  112. Elmenhorst D, Minuzzi L, Aliaga A, Rowley J, Massarweh G, Diksic M, et al. In vivo and in vitro validation of reference tissue models for the mGluR(5) ligand [11C]ABP688. J Cereb Blood Flow Metab. 2010;30:1538–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Elmenhorst D, Aliaga A, Bauer A, Rosa-Neto P. Test-retest stability of cerebral mGluR(5) quantification using [11C]ABP688 and positron emission tomography in rats. Synapse. 2012;66:552–60.

    Article  CAS  PubMed  Google Scholar 

  114. DeLorenzo C, Milak MS, Brennan KG, Kumar JS, Mann JJ, Parsey RV. In vivo positron emission tomography imaging with [11C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons. Eur J Nucl Med Mol Imaging. 2011;38:1083–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. DeLorenzo C, Kumar JS, 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;31:2169–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Miyake N, Skinbjerg M, Easwaramoorthy B, Kumar D, Girgis RR, Xu X, et al. Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C]ABP688 and N-acetylcysteine challenge. Biol Psychiatry. 2011;69:822–4.

    Article  CAS  PubMed  Google Scholar 

  117. Wyckhuys T, Verhaeghe J, Wyffels L, Langlois X, Schmidt M, Stroobants S, et al. N-acetylcysteine- and MK-801-induced changes in glutamate levels do not affect in vivo binding of metabotropic glutamate 5 receptor radioligand [11C]ABP688 in rat brain. J Nucl Med. 2013;54:1954–61.

    Article  CAS  PubMed  Google Scholar 

  118. Sandiego CM, Nabulsi N, Lin SF, Labaree D, Najafzadeh S, Huang Y, et al. Studies of the metabotropic glutamate receptor 5 radioligand [11C]ABP688 with N-acetylcysteine challenge in rhesus monkeys. Synapse. 2013;67:489–501.

    Article  CAS  PubMed  Google Scholar 

  119. Choi H, Kim YK, Oh SW, Im HJ, Hwang do W, Kang H, et al. In vivo imaging of mGluR5 changes during epileptogenesis using [11C]ABP688 PET in pilocarpine-induced epilepsy rat model. PLoS One. 2014;9:e92765.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65:1–105.

    Article  CAS  PubMed  Google Scholar 

  121. Mehta A, Prabhakar M, Kumar P, Deshmukh R, Sharma PL. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol. 2013;698:6–18.

    Article  CAS  PubMed  Google Scholar 

  122. Mark LP, Prost RW, Ulmer JL, Smith MM, Daniels DL, Strottmann JM, et al. Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging. AJNR Am J Neuroradiol. 2001;22:1813–24.

    CAS  PubMed  Google Scholar 

  123. Zimmer ER, Parent MJ, Leuzy A, Aliaga A, Aliaga A, Moquin L, et al. Imaging in vivo glutamate fluctuations with [11C]ABP688: a GLT-1 challenge with ceftriaxone. J Cereb Blood Flow Metab. 2015;35:1169–74.

    Article  CAS  PubMed  Google Scholar 

  124. Mathews WB, Kuwabara H, Stansfield K, Valentine H, Alexander M, Kumar A, et al. Dose-dependent, saturable occupancy of the metabotropic glutamate subtype 5 receptor by fenobam as measured with [11C]ABP688 PET imaging. Synapse. 2014.

  125. 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;48:247–52.

    CAS  PubMed  Google Scholar 

  126. Treyer V, Streffer J, Ametamey SM, Bettio A, Blauenstein P, Schmidt M, et al. Radiation dosimetry and biodistribution of [11C]ABP688 measured in healthy volunteers. Eur J Nucl Med Mol Imaging. 2008;35:766–70.

    Article  CAS  PubMed  Google Scholar 

  127. Akkus F, Terbeck S, Ametamey SM, Rufer M, Treyer V, Burger C, et al. Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder. Int J Neuropsychopharmacol. 2014;17:1915–22.

    Article  CAS  PubMed  Google Scholar 

  128. Akkus F, Treyer V, Johayem A, Ametamey SM, Mancilla BG, Sovago J, et al. Association of Long-Term Nicotine Abstinence with Normal Metabotropic Glutamate Receptor-5 Binding. Biol Psychiatry. 2015.

  129. Akkus F, Ametamey SM, Treyer V, Burger C, Johayem A, Umbricht D, et al. Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography. Proc Natl Acad Sci USA. 2013;110:737–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hulka LM, Treyer V, Scheidegger M, Preller KH, Vonmoos M, Baumgartner MR, et al. Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans. Mol Psychiatry. 2014;19:625–32.

    Article  CAS  PubMed  Google Scholar 

  131. Milella MS, Marengo L, Larcher K, Fotros A, Dagher A, Rosa-Neto P, et al. Limbic system mGluR5 availability in cocaine dependent subjects: a high-resolution PET [11C]ABP688 study. Neuroimage. 2014;98:195–202.

    Article  CAS  PubMed  Google Scholar 

  132. Leuzy A, Zimmer ER, Dubois J, Pruessner J, Cooperman C, Soucy JP, et al. In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD. Brain Struct Funct. 2015.

  133. DeLorenzo C, DellaGioia N, Bloch M, Sanacora G, Nabulsi N, Abdallah C, et al. In vivo ketamine-induced changes in [11C]ABP688 binding to metabotropic glutamate receptor subtype 5. Biol Psychiatry. 2015;77:266–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hefti K, Holst SC, Sovago J, Bachmann V, Buck A, Ametamey SM, et al. Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep. Biol Psychiatry. 2013;73:161–8.

    Article  CAS  PubMed  Google Scholar 

  135. Kawamura K, Yamasaki T, Kumata K, Furutsuka K, Takei M, Wakizaka H, et al. Binding potential of (E)-[11C]ABP688 to metabotropic glutamate receptor subtype 5 is decreased by the inclusion of its 11C-labelled Z-isomer. Nucl Med Biol. 2014;41:17–23.

    Article  CAS  PubMed  Google Scholar 

  136. 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;34:973–80.

    Article  CAS  PubMed  Google Scholar 

  137. 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;36:613–22.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  139. Sephton SM, Dennler P, Leutwiler DS, Mu L, Schibli R, Kramer SD, et al. Development of [18F]-PSS223 as a PET tracer for imaging of metabotropic glutamate receptor subtype 5 (mGluR5). Chimia (Aarau). 2012;66:201–4.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Sephton SM, Herde AM, Mu L, Keller C, Rudisuhli S, Auberson Y, 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. 2015;42:128–37.

    Article  CAS  PubMed  Google Scholar 

  142. Muller Herde A, Keller C, Milicevic Sephton S, Mu L, Schibli R, Ametamey SM, et al. Quantitative positron emission tomography of mGluR5 in rat brain with [18F]PSS232 at minimal invasiveness and reduced model complexity. J Neurochem. 2015;133:330–42.

    Article  PubMed  CAS  Google Scholar 

  143. 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;56:984–91.

    Article  CAS  PubMed  Google Scholar 

  144. Andersson JD, Seneca N, Truong P, Wensbo D, Raboisson P, Farde L, et al. Palladium mediated 11C-cyanation and characterization in the non-human primate brain of the novel mGluR5 radioligand [11C]AZD9272. Nucl Med Biol. 2013;40:547–53.

    Article  CAS  PubMed  Google Scholar 

  145. Kagedal M, Cselenyi Z, Nyberg S, Jonsson S, Raboisson P, Stenkrona P, et al. Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers. Neuroimage. 2012;61:849–56.

    Article  PubMed  Google Scholar 

  146. Pike VW. PET radiotracers: crossing the blood–brain barrier and surviving metabolism. Trends Pharmacol Sci. 2009;30:431–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wong DF, Pomper MG. Predicting the success of a radiopharmaceutical for in vivo imaging of central nervous system neuroreceptor systems. Mol Imaging Biol. 2003;5:350–62.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Stony Brook University Health Science Center for providing literature survey facilities and The Research Foundation for the State University of New York for providing financial assistance.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Stony Brook University Health Science Center, Stony Brook, NY, USA

    Rajapillai L. I. Pillai & Dnyanesh N. Tipre

Authors
  1. Rajapillai L. I. Pillai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dnyanesh N. Tipre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dnyanesh N. Tipre.

Ethics declarations

Conflict of interest

None.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pillai, R.L.I., Tipre, D.N. Metabotropic glutamate receptor 5 – a promising target in drug development and neuroimaging. Eur J Nucl Med Mol Imaging 43, 1151–1170 (2016). https://doi.org/10.1007/s00259-015-3301-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-015-3301-5

Keywords

Search

Navigation