Longitudinal PET Imaging of α7 Nicotinic Acetylcholine Receptors with [18F]ASEM in a Rat Model of Parkinson’s Disease

  • Steven Vetel
  • Johnny Vercouillie
  • Frédéric Buron
  • Jackie Vergote
  • Clovis Tauber
  • Julie Busson
  • Gabrielle Chicheri
  • Sylvain Routier
  • Sophie Sérrière
  • Sylvie ChalonEmail author
Research Article



The nicotinic acetylcholine alpha-7 receptors (α7R) are involved in a number of neuropsychiatric and neurodegenerative brain disorders such as Parkinson’s disease (PD). However, their specific pathophysiologic roles are still unclear. In this context, we studied the evolution of these receptors in vivo by positron emission tomography (PET) imaging using the recently developed tracer 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluorodibenzo[b,d]thiophene-5,5-dioxide) in a rat model mimicking early stages of PD.


PET imaging of α7R was performed at 3, 7, and 14 days following a partial striatal unilateral lesion with 6-hydroxydopamine in adult rats. After the last imaging experiments, the status of nigro-striatal dopamine neurons as well as different markers of neuroinflammation was evaluated on brain sections by autoradiographic and immunofluorescent experiments.


We showed an early and transitory rise in α7R expression in the lesioned striatum and substantia nigra, followed by over-expression of several gliosis activation markers in these regions of interest.


These findings support a longitudinally follow-up of α7R in animal models of PD and highlight the requirement to use a potential neuroprotective approach through α7R ligands at the early stages of PD.

Key words

Dopamine neurotransmission Neurodegeneration Neuroinflammation Microglia M1/M2 phenotype 



We thank the Laboratories Cyclopharma for providing fluor-18 and Sylvie Bodard for technical assistance.

Funding Information

This work was supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 278850 (INMiND), by Labex IRON (ANR-11-LABX-18-01), and by the Région Centre-Val de Loire project BIAlz (No. 2014 00091547).

Compliance with Ethical Standards

All procedures were conducted in accordance with the requirements of the European Community Council Directive 2010/63/EU for the care of laboratory animals and with the authorization of the Regional Ethical Committee (Authorization No. 2016.022218004689 and No. 00434.02).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

11307_2019_1400_MOESM1_ESM.pdf (176 kb)
ESM 1 (PDF 175 kb)


  1. 1.
    Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD (2010) Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des 16:323–343CrossRefGoogle Scholar
  2. 2.
    Dineley KT, Pandya AA, Yakel JL (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 36:96–108CrossRefGoogle Scholar
  3. 3.
    Fan H, Gu R, Wei D (2015) The alpha7 nAChR selective agonists as drug candidates for Alzheimer’s disease. Adv Exp Med Biol 827:353–365CrossRefGoogle Scholar
  4. 4.
    Quik M, Zhang D, McGregor M, Bordia T (2015) Alpha7 nicotinic receptors as therapeutic targets for Parkinson’s disease. Biochem Pharmacol 97:399–407CrossRefGoogle Scholar
  5. 5.
    Kalkman HO, Feuerbach D (2016) Modulatory effects of alpha7 nAChRs on the immune system and its relevance for CNS disorders. Cell Mol Life Sci 73:2511–2530CrossRefGoogle Scholar
  6. 6.
    Brust P, Peters D, Deuther-Conrad W (2012) Development of radioligands for the imaging of alpha7 nicotinic acetylcholine receptors with positron emission tomography. Curr Drug Targets 13:594–601CrossRefGoogle Scholar
  7. 7.
    Chalon S, Vercouillie J, Guilloteau D, Suzenet F, Routier S (2015) PET tracers for imaging brain alpha7 nicotinic receptors: an update. Chem Commun (Camb) 51:14826–14831CrossRefGoogle Scholar
  8. 8.
    Gao Y, Kellar KJ, Yasuda RP, Tran T, Xiao Y, Dannals RF, Horti AG (2013) Derivatives of dibenzothiophene for positron emission tomography imaging of alpha7-nicotinic acetylcholine receptors. J Med Chem 56:7574–7589CrossRefGoogle Scholar
  9. 9.
    Hillmer AT, Li S, Zheng MQ, Scheunemann M, Lin SF, Nabulsi N, Holden D, Pracitto R, Labaree D, Ropchan J, Teodoro R, Deuther-Conrad W, Esterlis I, Cosgrove KP, Brust P, Carson RE, Huang Y (2017) PET imaging of alpha7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans. Eur J Nucl Med Mol Imaging 44:1042–1050CrossRefGoogle Scholar
  10. 10.
    Coughlin JM, Du Y, Rosenthal HB et al (2018) The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: an in vivo positron emission tomography study with [18F]ASEM. Neuroimage 165:118–124CrossRefGoogle Scholar
  11. 11.
    Wong DF, Kuwabara H, Horti AG, Roberts JM, Nandi A, Cascella N, Brasic J, Weerts EM, Kitzmiller K, Phan JA, Gapasin L, Sawa A, Valentine H, Wand G, Mishra C, George N, McDonald M, Lesniak W, Holt DP, Azad BB, Dannals RF, Kem W, Freedman R, Gjedde A (2018) Brain PET imaging of alpha7-nAChR with [18F]ASEM: reproducibility, occupancy, receptor density, and changes in schizophrenia. Int J Neuropsychopharmacol 21:656–667CrossRefGoogle Scholar
  12. 12.
    Sérrière S, Doméné A, Vercouillie J et al (2015) Assessment of the protection of dopaminergic neurons by an α7 nicotinic receptor agonist, PHA543613 using [18F]LBT-999 in a Parkinson’s disease rat model. Front Med 2:61CrossRefGoogle Scholar
  13. 13.
    Chalon S, Garreau L, Emond P et al (1999) Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl)nortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J Pharmacol Exp Ther 291:648–654Google Scholar
  14. 14.
    Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates. Elsevier Academic Press, San DiegoGoogle Scholar
  15. 15.
    Bertrand D, Chih-Hung LL, Flood D et al (2015) Therapeutic potential of α7 nicotinic acetylcholine receptors. Pharmacol Rev 67:1025–1073CrossRefGoogle Scholar
  16. 16.
    Bertrand D, Terry AV (2018) The wonderland of neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 151:214–225CrossRefGoogle Scholar
  17. 17.
    Bordia T, McGregor M, Papke RL, Decker MW, Michael McIntosh J, Quik M (2015) The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions. Exp Neurol 263:277–284CrossRefGoogle Scholar
  18. 18.
    Horti AG (2015) Development of [18F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomography. Biochem Pharmacol 97:566–575CrossRefGoogle Scholar
  19. 19.
    Clarke PB, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-alpha-bungarotoxin. J Neurosci 5:1307–1345CrossRefGoogle Scholar
  20. 20.
    Whiteaker P, Davies AR, Marks MJ et al (1999) An autoradiographic study of the distribution of binding sites for the novel alpha7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain. Eur J Neurosci 11:2689–2696CrossRefGoogle Scholar
  21. 21.
    Vetel S, Serriere S, Vercouillie J et al (2019) Extensive exploration of a novel rat model of Parkinson’s disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches. Synapse 73:e22077CrossRefGoogle Scholar
  22. 22.
    Vingill S, Connor-Robson N, Wade-Martins R (2017) Are rodent models of Parkinson’s disease behaving as they should? Behav Brain Res 352:133–141CrossRefGoogle Scholar
  23. 23.
    Hemshekhar M, Anaparti V, Hitchon C, Mookherjee N (2017) Buprenorphine alters inflammatory and oxidative stress molecular markers in arthritis. Mediat Inflamm 2017:2515408CrossRefGoogle Scholar
  24. 24.
    Chakfe Y, Seguin R, Antel JP, Morissette C, Malo D, Henderson D, Séguéla P (2002) ADP and AMP induce interleukin-1beta release from microglial cells through activation of ATP-primed P2X7 receptor channels. J Neurosci 22:3061–3069CrossRefGoogle Scholar
  25. 25.
    Apolloni S, Amadio S, Parisi C, Matteucci A, Potenza RL, Armida M, Popoli P, D’Ambrosi N, Volonte C (2014) Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. Dis Model Mech 7:1101–1109CrossRefGoogle Scholar
  26. 26.
    Higashi Y, Aratake T, Shimizu S, Shimizu T, Nakamura K, Tsuda M, Yawata T, Ueba T, Saito M (2017) Influence of extracellular zinc on M1 microglial activation. Sci Rep 7:43778CrossRefGoogle Scholar
  27. 27.
    Casteels C, Vermaelen P, Nuyts J et al (2006) Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. J Nucl Med 47:1858–1866Google Scholar
  28. 28.
    Sérrière S, Tauber C, Vercouillie J, Guilloteau D, Deloye JB, Garreau L, Galineau L, Chalon S (2014) In vivo PET quantification of the dopamine transporter in rat brain with [18F]LBT-999. Nucl Med Biol 41:106–113CrossRefGoogle Scholar
  29. 29.
    Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415CrossRefGoogle Scholar
  30. 30.
    Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89:337–343CrossRefGoogle Scholar
  31. 31.
    Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E (2003) Alzheimer’s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Glia 41:207–211CrossRefGoogle Scholar
  32. 32.
    Zhang Q, Lu Y, Bian H et al (2017) Activation of the alpha7 nicotinic receptor promotes lipopolysaccharide-induced conversion of M1 microglia to M2. Am J Transl Res 9:971–985Google Scholar
  33. 33.
    Ambrosi G, Kustrimovic N, Siani F, Rasini E, Cerri S, Ghezzi C, Dicorato G, Caputo S, Marino F, Cosentino M, Blandini F (2017) Complex changes in the innate and adaptive immunity accompany progressive degeneration of the nigrostriatal pathway induced by Intrastriatal injection of 6-hydroxydopamine in the rat. Neurotox Res 32:71–81CrossRefGoogle Scholar
  34. 34.
    Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 8:174CrossRefGoogle Scholar
  35. 35.
    Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070CrossRefGoogle Scholar

Copyright information

© World Molecular Imaging Society 2019

Authors and Affiliations

  • Steven Vetel
    • 1
  • Johnny Vercouillie
    • 1
    • 2
  • Frédéric Buron
    • 3
  • Jackie Vergote
    • 1
  • Clovis Tauber
    • 1
  • Julie Busson
    • 1
  • Gabrielle Chicheri
    • 1
  • Sylvain Routier
    • 3
  • Sophie Sérrière
    • 1
  • Sylvie Chalon
    • 1
    Email author
  1. 1.UMR Inserm U1253, iBrainUniversité de Tours, UFR de MédecineTours Cedex 01France
  2. 2.INSERM CIC 1415University HospitalToursFrance
  3. 3.Institut de Chimie Organique et Analytique, ICOA, UMR CNRS 7311Université d’OrléansOrleansFrance

Personalised recommendations