Skip to content
2000
Volume 23, Issue 9
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Introduction

data from primates provide conflicting evidence about the suitability of the cerebellum as a reference region for quantifying type 5 metabotropic glutamate receptor (mGluR5) binding parameters with positron emission tomography (PET).

Methods

We first measured mGluR5 density in postmortem human cerebellum using [3H]ABP688 autoradiography (n=5) and immunohistochemistry (n=6). Next, experiments were conducted in healthy volunteers (n=6) using a high-resolution PET scanner (HRRT) to compare [11C]ABP688 binding potential (BP) values obtained with reference tissue methods and the two-tissue compartment model metabolite-corrected arterial input function.

Results

The postmortem data showed that, relative to the hippocampus, the cerebellum had 35% less mGluR5 immunoreactivity and 94% fewer [3H]ABP688 binding sites. brain regional [11C]ABP688 BP values using the cerebellum as a reference region were highly correlated with BP values and distribution volumes derived by arterial input methods (R2 > 0.9).

Conclusion

The scarce availability of cerebellar allosteric binding sites at autoradiography, compared to immunohistochemistry results, might reflect the presence of distinct mGluR5 isoforms or conformational state. Together with our PET data, these data support the proposition that [11C]ABP688 BP using the cerebellum as a reference region provides accurate quantification of mGluR5 allosteric binding . Studies relying on this method could, therefore, be used in clinical populations, providing that stronger initial assumptions are met.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cn/10.2174/1570159X23666250127161855
2025-02-18
2025-10-14

  • From This Site

    /content/journals/cn/10.2174/1570159X23666250127161855
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. KewJ.N.C. KempJ.A. Ionotropic and metabotropic glutamate receptor structure and pharmacology.Psychopharmacology2005179142910.1007/s00213‑005‑2200‑z 15731895
     [Google Scholar]
  2. GaspariniF. BilbeG. Gomez-MancillaB. SpoorenW. mGluR5 antagonists: Discovery, characterization and drug development.Curr. Opin. Drug Discov. Devel.2008115655665 18729017
     [Google Scholar]
  3. ParameshwaranK. DhanasekaranM. SuppiramaniamV. Amyloid beta peptides and glutamatergic synaptic dysregulation.Exp. Neurol.2008210171310.1016/j.expneurol.2007.10.008 18053990
     [Google Scholar]
  4. SpoorenW.P. VassoutA. NeijtH.C. KuhnR. GaspariniF. RouxS. PorsoltR.D. GentschC. Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents.J. Pharmacol. Exp. Ther.2000295312671275 11082464
     [Google Scholar]
  5. BreysseN. BaunezC. SpoorenW. GaspariniF. AmalricM. Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism.J. Neurosci.200222135669567810.1523/JNEUROSCI.22‑13‑05669.2002 12097518
     [Google Scholar]
  6. CoxS.M.L. TipplerM. JaworskaN. SmartK. Castellanos-RyanN. DurandF. AllardD. BenkelfatC. ParentS. DagherA. VitaroF. BoivinM. PihlR.O. CôtéS. TremblayR.E. SéguinJ.R. LeytonM. mGlu5 receptor availability in youth at risk for addictions: Effects of vulnerability traits and cannabis use.Neuropsychopharmacology202045111817182510.1038/s41386‑020‑0708‑x 32413893
     [Google Scholar]
  7. MilellaM.S. MarengoL. LarcherK. FotrosA. DagherA. Rosa-NetoP. BenkelfatC. LeytonM. Limbic system mGluR5 availability in cocaine dependent subjects: A high-resolution PET [11C]ABP688 study.Neuroimage20149819520210.1016/j.neuroimage.2014.04.061 24795154
     [Google Scholar]
  8. MartinezD. SlifsteinM. NabulsiN. GrassettiA. UrbanN.B.L. PerezA. LiuF. LinS.F. RopchanJ. MaoX. KegelesL.S. ShunguD.C. CarsonR.E. HuangY. Imaging glutamate homeostasis in cocaine addiction with the metabotropic glutamate receptor 5 positron emission tomography radiotracer [11C]ABP688 and magnetic resonance spectroscopy.Biol. Psychiatry201475216517110.1016/j.biopsych.2013.06.026 24035345
     [Google Scholar]
  9. AkkusF. AmetameyS.M. TreyerV. BurgerC. JohayemA. UmbrichtD. Gomez MancillaB. SovagoJ. BuckA. HaslerG. Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography.Proc. Natl. Acad. Sci. USA2013110273774210.1073/pnas.1210984110 23248277
     [Google Scholar]
  10. ChiamuleraC. Epping-JordanM.P. ZocchiA. MarconC. CottinyC. TacconiS. CorsiM. OrziF. ConquetF. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.Nat. Neurosci.20014987387410.1038/nn0901‑873 11528416
     [Google Scholar]
  11. BrunoV. BattagliaG. CopaniA. D’OnofrioM. Di IorioP. De BlasiA. MelchiorriD. FlorP.J. NicolettiF. Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs.J. Cereb. Blood Flow Metab.20012191013103310.1097/00004647‑200109000‑00001 11524608
     [Google Scholar]
  12. GladdingC.M. FitzjohnS.M. MolnárE. Metabotropic glutamate receptor-mediated long-term depression: Molecular mechanisms.Pharmacol. Rev.200961439541210.1124/pr.109.001735 19926678
     [Google Scholar]
  13. AmetameyS.M. TreyerV. StrefferJ. WyssM.T. SchmidtM. BlagoevM. HintermannS. AubersonY. GaspariniF. FischerU.C. BuckA. Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688.J. Nucl. Med.2007482247252 17268022
     [Google Scholar]
  14. LiW. WangY. LohithT.G. ZengZ. TongL. MazzolaR. RiffelK. MillerP. PurcellM. HolahanM. HaleyH. GantertL. HeskD. RenS. MorrowJ. UslanerJ. StruykA. WaiJ.M.C. RuddM.T. TellersD.M. McAvoyT. BormansG. KooleM. Van LaereK. SerdonsK. de HoonJ. DeclercqR. De LepeleireI. PascualM.B. Zanotti-FregonaraP. YuM. ArbonesV. MasdeuJ.C. ChengA. HussainA. BuetersT. AndersonM.S. HostetlerE.D. BasileA.S. The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer’s disease.Sci. Transl. Med.202214627eabg368410.1126/scitranslmed.abg3684 35020407
     [Google Scholar]
  15. HintermannS. VranesicI. AllgeierH. BrülisauerA. HoyerD. LemaireM. MoeniusT. UrwylerS. WhitebreadS. GaspariniF. AubersonY.P. ABP688, a novel selective and high affinity ligand for the labeling of mGlu5 receptors: Identification, in vitro pharmacology, pharmacokinetic and biodistribution studies.Bioorg. Med. Chem.200715290391410.1016/j.bmc.2006.10.038 17110115
     [Google Scholar]
  16. ElmenhorstD. MinuzziL. AliagaA. RowleyJ. MassarwehG. DiksicM. BauerA. Rosa-NetoP. In vivo and in vitro validation of reference tissue models for the mGluR(5) ligand [11C]ABP688.J. Cereb. Blood Flow Metab.20103081538154910.1038/jcbfm.2010.65 20531460
     [Google Scholar]
  17. ShigemotoR. NomuraS. OhishiH. SugiharaH. NakanishiS. MizunoN. Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain.Neurosci. Lett.19931631535710.1016/0304‑3940(93)90227‑C 8295733
     [Google Scholar]
  18. DeLorenzoC. KumarJ.S.D. MannJ.J. ParseyR.V. In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and [11C]ABP688.J. Cereb. Blood Flow Metab.201131112169218010.1038/jcbfm.2011.105 21792244
     [Google Scholar]
  19. TreyerV. StrefferJ. WyssM.T. BettioA. AmetameyS.M. FischerU. SchmidtM. GaspariniF. HockC. BuckA. Evaluation of the metabotropic glutamate receptor subtype 5 using PET and 11C-ABP688: Assessment of methods.J. Nucl. Med.20074871207121510.2967/jnumed.107.039578 17574984
     [Google Scholar]
  20. DeLorenzoC. MilakM.S. BrennanK.G. KumarJ.S.D. MannJ.J. ParseyR.V. 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. Imaging201138610831094[b]10.1007/s00259‑010‑1723‑721279350
     [Google Scholar]
  21. MiyakeN. SkinbjergM. EaswaramoorthyB. KumarD. GirgisR.R. XuX. SlifsteinM. Abi-DarghamA. Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C] ABP688 and N-acetylcysteine challenge.Biol. Psychiatry201169982282410.1016/j.biopsych.2010.12.023 21288506
     [Google Scholar]
  22. WyssM.T. AmetameyS.M. TreyerV. BettioA. BlagoevM. KesslerL.J. BurgerC. WeberB. SchmidtM. GaspariniF. BuckA. Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and a beta-scintillator.Neuroimage20073531086109210.1016/j.neuroimage.2007.01.005 17320417
     [Google Scholar]
  23. AmetameyS.M. KesslerL.J. HonerM. WyssM.T. BuckA. HintermannS. AubersonY.P. GaspariniF. SchubigerP.A. Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5.J. Nucl. Med.2006474698705 16595505
     [Google Scholar]
  24. PatelS. HamillT.G. ConnollyB. JagodaE. LiW. GibsonR.E. Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F]F-PEB.Nucl. Med. Biol.20073481009101710.1016/j.nucmedbio.2007.07.009 17998106
     [Google Scholar]
  25. LiberatoreG.T. WongJ.Y.F. KrenusD. JeffreysB.J. PorrittM.J. HowellsD.W. Tissue fixation prevents contamination of tritium-sensitive storage phosphor imaging plates.Biotechniques199926343243410.2144/99263bm13 10090979
     [Google Scholar]
  26. JongH.W.A.M. VeldenF.H.P. KloetR.W. BuijsF.L. BoellaardR. LammertsmaA.A. Performance evaluation of the ECAT HRRT: An LSO-LYSO double layer high resolution, high sensitivity scanner.Phys. Med. Biol.20075251505152610.1088/0031‑9155/52/5/019 17301468
     [Google Scholar]
  27. ReaderA.J. SureauF.C. ComtatC. TrébossenR. BuvatI. Joint estimation of dynamic PET images and temporal basis functions using fully 4D ML-EM.Phys. Med. Biol.200651215455547410.1088/0031‑9155/51/21/005 17047263
     [Google Scholar]
  28. CostesN. DagherA. LarcherK. EvansA.C. CollinsD.L. ReilhacA. Motion correction of multi-frame PET data in neuroreceptor mapping: Simulation based validation.Neuroimage20094741496150510.1016/j.neuroimage.2009.05.052 19481154
     [Google Scholar]
  29. InnisR.B. CunninghamV.J. DelforgeJ. FujitaM. GjeddeA. GunnR.N. HoldenJ. HouleS. HuangS.C. IchiseM. IidaH. ItoH. KimuraY. KoeppeR.A. KnudsenG.M. KnuutiJ. LammertsmaA.A. LaruelleM. LoganJ. MaguireR.P. MintunM.A. MorrisE.D. ParseyR. PriceJ.C. SlifsteinM. SossiV. SuharaT. VotawJ.R. WongD.F. CarsonR.E. Consensus nomenclature for in vivo imaging of reversibly binding radioligands.J. Cereb. Blood Flow Metab.20072791533153910.1038/sj.jcbfm.9600493 17519979
     [Google Scholar]
  30. KjærgaardK. FrischK. SørensenM. MunkO.L. HofmannA.F. HorsagerJ. SchachtA.C. EricksonM. ShapiroD. KeidingS. Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis.J. Hepatol.2021741586510.1016/j.jhep.2020.07.028 32717289
     [Google Scholar]
  31. LoganJ. FowlerJ.S. VolkowN.D. WolfA.P. DeweyS.L. SchlyerD.J. MacGregorR.R. HitzemannR. BendriemB. GatleyS.J. ChristmanD.R. 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.199010574074710.1038/jcbfm.1990.127 2384545
     [Google Scholar]
  32. LammertsmaA.A. HumeS.P. Simplified reference tissue model for PET receptor studies.Neuroimage19964315315810.1006/nimg.1996.0066 9345505
     [Google Scholar]
  33. LoganJ. FowlerJ.S. VolkowN.D. WangG.J. DingY.S. AlexoffD.L. Distribution volume ratios without blood sampling from graphical analysis of PET data.J. Cereb. Blood Flow Metab.199616583484010.1097/00004647‑199609000‑00008 8784228
     [Google Scholar]
  34. HamillT.G. KrauseS. RyanC. BonnefousC. GovekS. SeidersT.J. CosfordN.D.P. RoppeJ. KameneckaT. PatelS. GibsonR.E. SanabriaS. RiffelK. EngW. KingC. YangX. GreenM.D. O’malleyS.S. HargreavesR. BurnsH.D. Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers.Synapse200556420521610.1002/syn.20147 15803497
     [Google Scholar]
  35. BertheleA. PlatzerS. LaurieD.J. WeisS. SommerB. ZieglgänsbergerW. ConradB. TölleT.R. Expression of metabotropic glutamate receptor subtype mRNA (mGluR1-8) in human cerebellum.Neuroreport199910183861386710.1097/00001756‑199912160‑00026 10716224
     [Google Scholar]
  36. DaggettL.P. SacaanA.I. AkongM. RaoS.P. HessS.D. LiawC. UrrutiaA. JachecC. EllisS.B. DreessenJ. KnöpfelT. LandwehrmeyerG.B. TestaC.M. YoungA.B. VarneyM. JohnsonE.C. VeliçelebiG. Molecular and functional characterization of recombinant human metabotropic glutamate receptor subtype 5.Neuropharmacology199534887188610.1016/0028‑3908(95)00085‑K 8532169
     [Google Scholar]
  37. DeLorenzoC. GallezotJ.D. GardusJ. YangJ. PlanetaB. NabulsiN. OgdenR.T. LabareeD.C. HuangY.H. MannJ.J. GaspariniF. LinX. JavitchJ.A. ParseyR.V. CarsonR.E. EsterlisI. In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C]ABP688 and [18F]FPEB.J. Cereb. Blood Flow Metab.20173782716272710.1177/0271678X16673646 27742888
     [Google Scholar]
  38. DeLorenzoC. DellaGioiaN. BlochM. SanacoraG. NabulsiN. AbdallahC. YangJ. WenR. MannJ.J. KrystalJ.H. ParseyR.V. CarsonR.E. EsterlisI. In vivo ketamine-induced changes in [11C]ABP688 binding to metabotropic glutamate receptor subtype 5.Biol. Psychiatry201577326627510.1016/j.biopsych.2014.06.024 25156701
     [Google Scholar]
  39. GinovartN. WilleitM. RusjanP. GraffA. BloomfieldP.M. HouleS. KapurS. WilsonA.A. Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain.J. Cereb. Blood Flow Metab.200727485787110.1038/sj.jcbfm.9600411 17033687
     [Google Scholar]
  40. LammertsmaA.A. BenchC.J. HumeS.P. OsmanS. GunnK. BrooksD.J. FrackowiakR.S.J. Comparison of methods for analysis of clinical [11C]raclopride studies.J. Cereb. Blood Flow Metab.19961614252b]10.1097/00004647‑199601000‑000058530554
     [Google Scholar]
  41. AkkusF. TreyerV. JohayemA. AmetameyS.M. MancillaB.G. SovagoJ. BuckA. HaslerG. Association of long-term nicotine abstinence with normal metabotropic glutamate receptor-5 binding.Biol. Psychiatry201679647448010.1016/j.biopsych.2015.02.027
     [Google Scholar]
  42. SmartK. Nagano-SaitoA. MilellaM.S. SakaeD.Y. FavierM. VigneaultE. LouieL. HamiltonA. FergusonS.S.G. Rosa-NetoP. NarayananS. MestikawyS.E. LeytonM. BenkelfatC. Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans.J. Psychiatry Neurosci.2021461E1E1310.1503/jpn.190162 32559027
     [Google Scholar]
  43. ParseyR.V. SlifsteinM. HwangD.R. Abi-DarghamA. SimpsonN. MawlawiO. GuoN.N. Van HeertumR. MannJ.J. LaruelleM. Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: Comparison of arterial and reference tisssue input functions.J. Cereb. Blood Flow Metab.20002071111113310.1097/00004647‑200007000‑00011 10908045
     [Google Scholar]
  44. ChangeuxJ.P. EdelsteinS.J. Allosteric mechanisms of signal transduction.Science200530857271424142810.1126/science.1108595 15933191
     [Google Scholar]
  45. MalherbeP. KratochwilN. MühlemannA. ZennerM.T. FischerC. StahlM. GerberP.R. JaeschkeG. PorterR.H.P. Comparison of the binding pockets of two chemically unrelated allosteric antagonists of the mGlu5 receptor and identification of crucial residues involved in the inverse agonism of MPEP.J. Neurochem.200698260161510.1111/j.1471‑4159.2006.03886.x 16805850
     [Google Scholar]
  46. BdairH. Sato-FitoussiM. PlancheS. MoquinL. KangM.S. AliagaA. Nagano-SaitoA. SmartK. CoxS.M.L. NearJ. Aguilar-VallesA. MassarwehG. Rosa-NetoP. BenkelfatC. SoucyJ.P. KostikovA. GrattonA. LeytonM. Testing PET-[11C]ABP688 as a tool to quantify glutamate release in vivo.Imaging Neuroscience2024211810.1162/imag_a_00126
     [Google Scholar]
  47. MalherbeP. KewJ.N.C. RichardsJ.G. KnoflachF. KratzeisenC. ZennerM.T. FaullR.L.M. KempJ.A. MutelV. Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum.Brain Res. Mol. Brain Res.20021091-216817810.1016/S0169‑328X(02)00557‑0 12531526
     [Google Scholar]
  48. NarendranR. HwangD.R. SlifsteinM. TalbotP.S. ErritzoeD. HuangY. CooperT.B. MartinezD. KegelesL.S. Abi-DarghamA. LaruelleM. In vivo vulnerability to competition by endogenous dopamine: Comparison of the D2 receptor agonist radiotracer (–)‐N‐[11C]propyl‐norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]‐raclopride.Synapse200452318820810.1002/syn.20013 15065219
     [Google Scholar]
  49. EsterlisI. DellaGioiaN. PietrzakR.H. MatuskeyD. NabulsiN. AbdallahC.G. YangJ. PittengerC. SanacoraG. KrystalJ.H. ParseyR.V. CarsonR.E. DeLorenzoC. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: An [11C]ABP688 and PET imaging study in depression.Mol. Psychiatry201823482483210.1038/mp.2017.58 28397841
     [Google Scholar]
  50. KågedalM. CselényiZ. NybergS. RaboissonP. StåhleL. StenkronaP. VarnäsK. HalldinC. HookerA.C. KarlssonM.O. A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 - Estimating occupancy in the absence of a reference region.Neuroimage20138216016910.1016/j.neuroimage.2013.05.006 23668965
     [Google Scholar]
/content/journals/cn/10.2174/1570159X23666250127161855
Loading
Quantification of [11C]ABP688 Binding to mGluR5 in Human Brain using Cerebellum as Reference Region: Biological Interpretation and Limitations
Curr. Neuropharmacol. 23, 1081 (2025); https://doi.org/10.2174/1570159X23666250127161855
/content/journals/cn/10.2174/1570159X23666250127161855
/content/journals/cn/10.2174/1570159X23666250127161855
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): [11C]ABP688; autoradiography; kinetic modeling; mGluR5; positron emission tomography; receptor imaging

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test