Skip to main content

Advertisement

SpringerLink
Log in

Molecular imaging of α7 nicotinic acetylcholine receptors: design and evaluation of the potent radioligand [18F]NS10743

  • Original article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The outstanding diversity of cellular properties mediated by neuronal and nonneuronal α7 nicotinic acetylcholine receptors (α7 nAChR) points to the diagnostic potential of quantitative nuclear molecular imaging of α7 nAChR in neurology and oncology. It was our goal to radiolabel the α7 nAChR agonist 4-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane (NS10743) and to assess the selectivity of [18F]NS10743 binding site occupancy in animal experiments.

Methods

[18F]NS10743 was synthesized by nucleophilic substitution of the nitro precursor. In vitro receptor affinity and selectivity were assessed by radioligand competition and autoradiography. The radiotracer properties were evaluated in female CD-1 mice by brain autoradiography and organ distribution. Target specificity was validated after treatment with SSR180711 (10 mg/kg, intraperitoneal), and metabolic stability was investigated using radio-HPLC.

Results

The specific activity of [18F]NS10743 exceeded 150 GBq/μmol at a radiochemical purity >99%. In vitro, NS10743 and [18F]NS10743 showed high affinity and specificity towards α7 nAChR. The brain permeation of [18F]NS10743 was fast and sufficient with values of 4.83 and 1.60% injected dose per gram and brain to plasma ratios of 3.83 and 2.05 at 5 and 60 min after radiotracer administration. Brain autoradiography and organ distribution showed target-specific accumulation of [18F]NS10743 in brain substructures and various α7 nAChR-expressing organs. The radiotracer showed a high metabolic stability in vivo with a single polar radiometabolite, which did not cross the blood–brain barrier.

Conclusion

The good in vitro and in vivo features of [18F]NS10743 make this radioligand a promising candidate for quantitative in vivo imaging of α7 nAChR expression and encourage further investigations.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Dominguez del Toro E, Juiz JM, Peng X, Lindström J, Criado M. Immunocytochemical localization of the α7 subunit of the nicotinic acetylcholine receptor in the rat central nervous system. J Comp Neurol 1994;349:325–42.

    Article  PubMed  CAS  Google Scholar 

  2. Dajas-Bailador F, Wonnacott S. Nicotinic acetylcholine receptors and the regulation of neuronal signalling. Trends Pharmacol Sci 2004;25:317–24.

    Article  PubMed  CAS  Google Scholar 

  3. Jensen AA, Frolund B, Liljefors T, Krogsgaard-Larsen P. Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. J Med Chem 2005;48:4705–45.

    Article  PubMed  CAS  Google Scholar 

  4. Gahring LC, Rogers SW. Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells. AAPS J 2006;7:E885–94.

    Article  PubMed  Google Scholar 

  5. Sharma G, Vijayaraghavan S. Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores. Proc Natl Acad Sci U S A 2001;98:4148–53.

    Article  PubMed  CAS  Google Scholar 

  6. Teaktong T, Graham AJ, Court JA, Perry RH, Jaros E, Johnson M, et al. Nicotinic acetylcholine receptor immunohistochemistry in Alzheimer’s disease and dementia with Lewy bodies: differential neuronal and astroglial pathology. J Neurol Sci 2004;225:39–49.

    Article  PubMed  CAS  Google Scholar 

  7. Berg DK, Conroy WG. Nicotinic α7 receptors: synaptic options and downstream signaling in neurons. J Neurobiol 2002;53:512–23.

    Article  PubMed  CAS  Google Scholar 

  8. Dajas-Bailador FA, Mogg AJ, Wonnacott S. Intracellular Ca2+ signals evoked by stimulation of nicotinic acetylcholine receptors in SH-SY5Y cells: contribution of voltage-operated Ca2+ channels and Ca2+ stores. J Neurochem 2002;81:606–14.

    Article  PubMed  CAS  Google Scholar 

  9. Alkondon M, Pereira EF, Albuquerque EX. Age-dependent changes in the functional expression of two nicotinic receptor subtypes in CA1 stratum radiatum interneurons in the rat hippocampus. Biochem Pharmacol 2007;74:1134–44.

    Article  PubMed  CAS  Google Scholar 

  10. Breese CR, Adams C, Logel J, Drebing C, Rollins Y, Barnhart M, et al. Comparison of the regional expression of nicotinic acetylcholine receptor α7 mRNA and [125I]-α-bungarotoxin binding in human postmortem brain. J Comp Neurol 1997;387:385–98.

    Article  PubMed  CAS  Google Scholar 

  11. Wanaverbecq N, Semyanov A, Pavlov I, Walker MC, Kullmann DM. Cholinergic axons modulate GABAergic signaling among hippocampal interneurons via postsynaptic α7 nicotinic receptors. J Neurosci 2007;27:5683–93.

    Article  PubMed  CAS  Google Scholar 

  12. Hogg RC, Bertrand D. Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 2007;73:459–68.

    Article  PubMed  CAS  Google Scholar 

  13. Mudo G, Belluardo N, Fuxe K. Nicotinic receptor agonists as neuroprotective/neurotrophic drugs. Progress in molecular mechanisms. J Neural Transm 2007;114:135–47.

    Article  PubMed  CAS  Google Scholar 

  14. Burghaus L, Schütz U, Krempel U, de Vos RA, Jansen Steur EN, Wevers A, et al. Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients. Brain Res Mol Brain Res 2000;76:385–8.

    Article  PubMed  CAS  Google Scholar 

  15. Burghaus L, Schütz U, Krempel U, Lindstrom J, Schröder H. Loss of nicotinic acetylcholine receptor subunits α4 and α7 in the cerebral cortex of Parkinson patients. Parkinsonism Relat Disord 2003;9:243–6.

    PubMed  Google Scholar 

  16. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 2003;421:384–8.

    Article  PubMed  CAS  Google Scholar 

  17. Conejero-Goldberg C, Davies P, Ulloa L. Alpha7 nicotinic acetylcholine receptor: a link between inflammation and neurodegeneration. Neurosci Biobehav Rev 2008;32:693–706.

    Article  PubMed  CAS  Google Scholar 

  18. Faghih R, Gopalakrishnan M, Briggs CA. Allosteric modulators of the α7 nicotinic acetylcholine receptor. J Med Chem 2008;51:701–12.

    Article  PubMed  CAS  Google Scholar 

  19. Mazurov A, Hauser T, Miller CH. Selective α7 nicotinic acetylcholine receptor ligands. Curr Med Chem 2006;13:1567–84.

    Article  PubMed  CAS  Google Scholar 

  20. Egleton RD, Brown KC, Dasgupta P. Nicotinic acetylcholine receptors in cancer: multiple roles in proliferation and inhibition of apoptosis. Trends Pharmacol Sci 2008;29:151–8.

    PubMed  CAS  Google Scholar 

  21. Plummer HK 3rd, Dhar M, Schuller HM. Expression of the alpha7 nicotinic acetylcholine receptor in human lung cells. Respir Res 2005;6:29.

    Article  PubMed  Google Scholar 

  22. Wong HP, Yu L, Lam EK, Tai EK, Wu WK, Cho CH. Nicotine promotes cell proliferation via α7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells. Toxicol Appl Pharmacol 2007;221:261–7.

    Article  PubMed  CAS  Google Scholar 

  23. Summers AE, Whelan CJ, Parsons ME. Nicotinic acetylcholine receptor subunits and receptor activity in the epithelial cell line HT29. Life Sci 2003;72:2091–4.

    Article  PubMed  CAS  Google Scholar 

  24. Schuller HM. Neurotransmitter receptor-mediated signaling pathways as modulators of carcinogenesis. Prog Exp Tumor Res 2007;39:45–63.

    Article  PubMed  Google Scholar 

  25. Navarro HA, Zhong D, Abraham P, Xu H, Carroll FI. Synthesis and pharmacological characterization of [125I]iodomethyllycaconitine ([125I]Iodo-MLA). A new ligand for the α7 nicotinic acetylcholine receptor. J Med Chem 2000;43:142–5.

    Article  PubMed  CAS  Google Scholar 

  26. Navarro HA, Xu H, Zhong D, Abraham P, Carroll FI. In vitro and in vivo characterization of [125I]iodomethyllycaconitine in the rat. Synapse 2002;44:117–23.

    Article  PubMed  CAS  Google Scholar 

  27. Dolle F, Valette H, Hinnen F, Vaufrey F, Demphel S, Coulon C, et al. Synthesis and preliminary evaluation of a carbon-11-labelled agonist of the α7 nicotinic acetylcholine receptor. J Label Compd Radiopharm 2001;44:785–95.

    Article  CAS  Google Scholar 

  28. Pomper MG, Phillips E, Fan H, McCarthy DJ, Keith RA, Gordon JC, et al. Synthesis and biodistribution of radiolabeled α7 nicotinic acetylcholine receptor ligands. J Nucl Med 2005;46:326–34.

    PubMed  CAS  Google Scholar 

  29. Ogawa M, Tatsumi R, Fujio M, Katayama J, Magata Y. Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor α7 subtype imaging agent. Nucl Med Biol 2006;33:311–6.

    Article  PubMed  CAS  Google Scholar 

  30. Kim SW, Ding YS, Alexoff D, Patel V, Logan J, Lin KS, et al. Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial α7 nicotinic cholinergic agonist drug. Nucl Med Biol 2007;34:541–51.

    Article  PubMed  CAS  Google Scholar 

  31. Bunnelle WH, Dart MJ, Schrimpf MR. Design of ligands for the nicotinic acetylcholine receptors: the quest for selectivity. Curr Top Med Chem 2004;4:299–334.

    Article  PubMed  CAS  Google Scholar 

  32. Gallet T, Jegham S, Lardenois P, Lochead AW, Nedelec A. Preparation of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylates as nicotinic receptor ligands. 2000, WO/2000/058311. International Application No.: PCT/FR2000/000697.

  33. O’Donnell CJ, O’Neill BT. Preparation of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid esters and amides as CNS-penetrant α7 nicotinic receptor agonists. 2002, European Patent Application 1231212.

  34. Peters D, Olsen GM, Nielsen EO, Jorgensen TD, Ahring PK. Novel 1,4-diazabicycloalkane derivatives, their preparation and use. 2004, WO/2004/029053. International Application No.: PCT/DK2003/000639.

  35. Peters D, Olsen GM, Nielsen EO, Timmermann DB, Loechel SC, Mikkelsen JD, et al. Novel 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivatives and their medical use. 2007, WO/2007/138037. International Application No.: PCT/EP2007/055168

  36. Hashimoto K, Nishiyama S, Ohba H, Matsuo M, Kobashi T, Takahagi M, et al. [11C]CHIBA-1001 as a novel PET ligand for α7 nicotinic receptors in the brain: a PET study in conscious monkeys. PLoS ONE 2008;3:e3231.

    Article  PubMed  Google Scholar 

  37. Young RC, Mitchell RC, Brown TH, Ganellin CR, Griffiths R, Jones M, et al. Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J Med Chem 1988;31:656–71.

    Article  PubMed  CAS  Google Scholar 

  38. Deuther-Conrad W, Patt JT, Feuerbach D, Wegner F, Brust P, Steinbach J. Norchloro-fluoro-homoepibatidine: specificity to neuronal nicotinic acetylcholine receptor subtypes in vitro. Farmaco 2004;59:785–92.

    Article  PubMed  CAS  Google Scholar 

  39. Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 1973;22:3099–108.

    Article  PubMed  CAS  Google Scholar 

  40. Jeffries WB, Waugh D, Abel PW. Analysis of data from "Cold Saturation" radioligand binding experiments. Methods Mol Biol 1997;73:331–42.

    PubMed  CAS  Google Scholar 

  41. Michelmore S, Croskery K, Nozulak J, Hoyer D, Longato R, Weber A, et al. Study of the calcium dynamics of the human α4β2, α3β4 and α1β1γδ nicotinic acetylcholine receptors. Naunyn Schmiedebergs Arch Pharmacol 2002;366:235–45.

    Article  PubMed  CAS  Google Scholar 

  42. Biton B, Bergis OE, Galli F, Nedelec A, Lochead AW, Jegham S, et al. SSR180711, a novel selective α7 nicotinic receptor partial agonist: (I) Binding and functional profile. Neuropsychopharmacology 2007;32:1–16.

    Article  PubMed  CAS  Google Scholar 

  43. Motulsky HJ, Christopoulos A. Fitting models to biological data using linear and nonlinear regression. A practical guide to curve fitting. 2nd printing. San Diego, CA: GraphPad Software; 2003.

    Google Scholar 

  44. Washio T, Arisawa H, Kohsaka K, Yasuda H. Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull 2001;24:1263–6.

    Article  PubMed  CAS  Google Scholar 

  45. Shaffer CL, Gunduz M, Scialis RJ, Fang AF. Metabolism and disposition of a selective α7 nicotinic acetylcholine receptor agonist in humans. Drug Metab Dispos 2007;35:1188–95.

    Article  PubMed  CAS  Google Scholar 

  46. Tietje KR, Anderson DJ, Bitner RS, Blomme EA, Brackemeyer PJ, Briggs CA, et al. Preclinical characterization of A-582941: a novel α7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties. CNS Neurosci Ther 2008;14:65–82.

    Article  PubMed  CAS  Google Scholar 

  47. Lengyel K, Pieschl R, Strong T, Molski T, Mattson G, Lodge NJ, et al. Ex vivo assessment of binding site occupancy of monoamine reuptake inhibitors: methodology and biological significance. Neuropharmacology 2008;55:63–70.

    Article  PubMed  CAS  Google Scholar 

  48. Graham AJ, Ray MA, Perry EK, Jaros E, Perry RH, Volsen SG, et al. Differential nicotinic acetylcholine receptor subunit expression in the human hippocampus. J Chem Neuroanat 2003;25:97–113.

    Article  PubMed  CAS  Google Scholar 

  49. Quik M, Polonskaya Y, Gillespie A, Jakowec M, Lloyd GK, Langston JW. Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization. J Comp Neurol 2000;425:58–69.

    Article  PubMed  CAS  Google Scholar 

  50. Zhang X, Liu C, Miao H, Gong ZH, Nordberg A. Postnatal changes of nicotinic acetylcholine receptor α2, α3, α4, α7 and β2 subunits genes expression in rat brain. Int J Dev Neurosci 1998;16:507–18.

    Article  PubMed  CAS  Google Scholar 

  51. Whiteaker P, Davies AR, Marks MJ, Blagbrough IS, Potter BV, Wolstenholme AJ, et al. An autoradiographic study of the distribution of binding sites for the novel α7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain. Eur J Neurosci 1999;11:2689–96.

    Article  PubMed  CAS  Google Scholar 

  52. Terry AV Jr, Gearhart DA. Time dependent decreases in central α7 nicotinic acetylcholine receptors associated with haloperidol and risperidone treatment in rats. Eur J Pharmacol 2007;571:29–32.

    Article  PubMed  CAS  Google Scholar 

  53. Clarke PB, Schwartz RD, Paul SM, Pert CB, Pert A. Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-α-bungarotoxin. J Neurosci 1985;5:1307–15.

    PubMed  CAS  Google Scholar 

  54. Dominguez del Toro E, Juiz JM, Smillie FI, Lindstrom J, Criado M. Expression of α7 neuronal nicotinic receptors during postnatal development of the rat cerebellum. Brain Res Dev Brain Res 1997;98:125–33.

    Article  PubMed  CAS  Google Scholar 

  55. Graham A, Court JA, Martin-Ruiz CM, Jaros E, Perry R, Volsen SG, et al. Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum. Neuroscience 2002;113:493–507.

    Article  PubMed  CAS  Google Scholar 

  56. Sala F, Nistri A, Criado M. Nicotinic acetylcholine receptors of adrenal chromaffin cells. Acta Physiol (Oxf) 2008;192:203–12.

    CAS  Google Scholar 

  57. Skok M, Grailhe R, Agenes F, Changeux JP. The role of nicotinic acetylcholine receptors in lymphocyte development. J Neuroimmunol 2006;171:86–98.

    Article  PubMed  CAS  Google Scholar 

  58. Kirchgessner AL, Liu MT. Immunohistochemical localization of nicotinic acetylcholine receptors in the guinea pig bowel and pancreas. J Comp Neurol 1998;390:497–514.

    Article  PubMed  CAS  Google Scholar 

  59. Skok MV, Grailhe R, Agenes F, Changeux JP. The role of nicotinic receptors in B-lymphocyte development and activation. Life Sci 2007;80:2334–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Tina Ludwig for her technical assistance on the receptor binding assays and determination of distribution coefficients, and the staff of the Cyclotron Facility at the Department of Nuclear Medicine, University of Leipzig, for [18F]F− production.

Author information

Authors and Affiliations

  1. Institute of Interdisciplinary Isotope Research, Permoserstr. 15, 04318, Leipzig, Germany

    Winnie Deuther-Conrad, Steffen Fischer, Achim Hiller, Jörg Steinbach & Peter Brust

  2. NeuroSearch A/S, Ballerup, Denmark

    Elsebet Østergaard Nielsen, Daniel Brunicardi Timmermann & Dan Peters

  3. Department of Nuclear Medicine, Universität Leipzig, Leipzig, Germany

    Osama Sabri

  4. Institute of Radiopharmacy, Forschungszentrum Dresden-Rossendorf, Dresden, Germany

    Jörg Steinbach

Authors
  1. Winnie Deuther-Conrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steffen Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Achim Hiller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elsebet Østergaard Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Brunicardi Timmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jörg Steinbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Osama Sabri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dan Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter Brust
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Winnie Deuther-Conrad.

Additional information

Winnie Deuther-Conrad and Steffen Fischer contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deuther-Conrad, W., Fischer, S., Hiller, A. et al. Molecular imaging of α7 nicotinic acetylcholine receptors: design and evaluation of the potent radioligand [18F]NS10743. Eur J Nucl Med Mol Imaging 36, 791–800 (2009). https://doi.org/10.1007/s00259-008-1031-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-008-1031-7

Keywords

Search

Navigation