Nuclear Medicine and Biology
Volume 35, Issue 2 , Pages 185-195 , February 2008

A new 18F-labeled fluoroacetylmorpholino derivative of vesamicol for neuroimaging of the vesicular acetylcholine transporter

  • Dietlind Sorger

      Affiliations

    • Department of Nuclear Medicine, University of Leipzig, 04103 Leipzig, Germany
    • Corresponding Author InformationCorresponding author.
  • ,
  • Matthias Scheunemann

      Affiliations

    • Institute of Interdisciplinary Isotope Research, 04318 Leipzig, Germany
  • ,
  • Udo Großmann

      Affiliations

    • Department of Nuclear Medicine, University of Leipzig, 04103 Leipzig, Germany
  • ,
  • Steffen Fischer

      Affiliations

    • Institute of Interdisciplinary Isotope Research, 04318 Leipzig, Germany
  • ,
  • Johnny Vercouille

      Affiliations

    • Institute of Interdisciplinary Isotope Research, 04318 Leipzig, Germany
  • ,
  • Achim Hiller

      Affiliations

    • Institute of Interdisciplinary Isotope Research, 04318 Leipzig, Germany
  • ,
  • Barbara Wenzel

      Affiliations

    • Institute of Interdisciplinary Isotope Research, 04318 Leipzig, Germany
  • ,
  • Ali Roghani

      Affiliations

    • Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 39430, USA
  • ,
  • Reinhard Schliebs

      Affiliations

    • Paul-Flechsig Institute of Brain Research, University of Leipzig, 04109 Leipzig, Germany
  • ,
  • Peter Brust

      Affiliations

    • Institute of Interdisciplinary Isotope Research, 04318 Leipzig, Germany
  • ,
  • Osama Sabri

      Affiliations

    • Department of Nuclear Medicine, University of Leipzig, 04103 Leipzig, Germany
  • ,
  • Jörg Steinbach

      Affiliations

    • Institute of Interdisciplinary Isotope Research, 04318 Leipzig, Germany

Received 11 July 2007 ,Revised 24 August 2007 ,Accepted 10 October 2007.

References 

  1. Schliebs R, Arendt T. The significance of the cholinergic system in the brain during aging and in Alzheimer's disease. J Neural Transm. 2006;113:1625–1644
  2. Sivaprakasam K. Towards a unifying hypothesis of Alzheimer's disease: cholinergic system linked to plaques, tangles and neuroinflammation. Curr Med Chem. 2006;13:2179–2188
  3. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215:1237–1239
  4. Bowen DM, Smith CB, White P, Goodhardt MJ, Spillane JA, Flack RH, et al. Chemical pathology of organic dementias. I. Validity of biochemical measurements on human post-mortem brain specimens. Brain. 1977;100:397–426
  5. Etienne P, Robitaille Y, Wood P, Gauthier S, Nair NP, Quirion R. Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease. Neuroscience. 1986;19:1279–1291
  6. McGeer PL. The 12th J. A. F. Stevenson memorial lecture. Aging, Alzheimer's disease, and the cholinergic system. Can J Physiol Pharmacol. 1984;62:741–754
  7. Eiden LE. The cholinergic gene locus. J Neurochem. 1998;70:2227–2240
  8. Erickson JD, Varoqui H, Schäfer MKH, Modi W, Diebler MF, Weihe E, et al. Functional identification of a vesicular acetylcholine transporter and its expression from a "cholinergic" gene locus. J Biol Chem. 1994;269:21929–21932
  9. Roghani A, Carroll PT. Analysis of uptake and release of newly synthesized acetylcholine in PC12 cells overexpressing the rat vesicular acetylcholine transporter (VAChT). Brain Res Mol Brain Res. 2002;100:21–30
  10. Mallet J, Houhou L, Pajak F, Oda Y, Cervini R, Bejanin S, et al. The cholinergic locus: ChAT and VAChT genes. J Physiol Paris. 1998;92:145–147
  11. Sihver W, Gillberg PG, Svensson AL, Nordberg A. Autoradiographic comparison of [3H](−)nicotine, [3H]cytisine and [3H]epibatidine binding in relation to vesicular acetylcholine transport sites in the temporal cortex in Alzheimer's disease. Neuroscience. 1999;94:685–696
  12. Ikeda E, Shiba K, Mori H, Ichikawa A, Sumiya H, Kuji I, et al. Reduction of vesicular acetylcholine transporter in beta-amyloid protein-infused rats with memory impairment. Nucl Med Commun. 2000;21:933–937
  13. Altar CA, Marien MR. [3H]Vesamicol binding in brain: autoradiographic distribution, pharmacology, and effects of cholinergic lesions. Synapse. 1988;2:486–493
  14. Marien MR, Parsons SM, Altar CA. Quantitative autoradiography of brain binding sites fore the vesicular acetylcholine transport blocker 2-(4-phenylpiperidino)cyclohexanol (AH5183). Proc Natl Acad Sci. U S A. 1987;84:876–880
  15. Parsons SM, Bahr BA, Rogers GA, Clarkson ED, Noremberg K, Hicks BW. Acetylcholine transporter — vesamicol receptor pharmacology and structure. Prog Brain Res. 1993;98:175–181
  16. Rogers GA, Parsons SM, Anderson DC, Nilsson LM, Bahr BA, Kornreich WD, et al. Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogues of trans-2-(4-phenylpiperidino)cyclohexanol (Vesamicol). J Med Chem. 1989;32:1217–1230
  17. Browne SE, Lin L, Mattsson A, Georgievska B, Isacson O. Selective antibody-induced cholinergic cell and synapse loss produce sustained hippocampal and cortical hypometabolism with correlated cognitive deficits. Exp Neurol. 2001;170:36–47
  18. Sorger D, Schliebs R, Kampfer I, Rossner S, Heinicke J, Dannenberg C, et al. In vivo [125I]-iodobenzovesamicol binding reflects cortical cholinergic deficiency induced by specific immunolesion of rat basal forebrain cholinergic system. Nucl Med Biol. 2000;27:23–31
  19. Quinlivan M, Chalon S, Vergote J, Henderson J, Katsifis A, Kassiou M, et al. Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning. Neurosci Lett. 2007;415:97–101
  20. Kish SJ, Distefano LM, Dozic S, Robitaille Y, Rajput A, Deck JHN, et al. [3H]Vesamicol binding in human brain cholinergic deficiency disorders. Neurosci Lett. 1990;117:347–352
  21. Ruberg M, Mayo W, Brice A, Duyckaerts C, Hauw JJ, Simon H, et al. Choline acetyltransferase activity and [3H]Vesamicol binding in the temporal cortex of patients with Alzheimer's disease, Parkinson's disease, and rats with basal forebrain lesions. Neuroscience. 1990;35:327–333
  22. Efange SMN, Garland EM, Staley JK, Khare AB, Mash DC. Vesicular acetylcholine transporter density and Alzheimer's disease. Neurobiol Aging. 1997;18:407–413
  23. Kuhl DE, Koeppe RA, Fessler JA, Minoshima S, Ackermann RJ, Carey JE, et al. In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM. J Nucl Med. 1993;35:405–410
  24. Kuhl DE, Minoshima S, Fessler JA, Frey KA, Foster NL, Ficaro EP, et al. In vivo mapping of cholinergic terminals in normal aging. Alzheimer's disease and Parkinson's disease. Ann Neurol. 1996;40:399–410
  25. Cohen RM. The application of positron-emitting molecular imaging tracers in Alzheimer's disease. Mol Imaging Biol. 2007;9:204–216
  26. Custers FG, Leysen JE, Stoof JC, Herscheid JD. Vesamicol and some of its derivatives: questionable ligands for selectively labelling acetylcholine transporters in rat brain. Eur J Pharmacol. 1997;338:177–183
  27. Efange SM, Mach RH, Smith CR, Khare AB, Foulon C, Akella SK, et al. Vesamicol analogues as sigma ligands. Molecular determinants of selectivity at the vesamicol receptor. Biochem Pharmacol. 1995;49:791–797
  28. Bando K, Naganuma T, Taguchi K, Ginoza Y, Tanaka Y, Koike K, et al. Piperazine analog of vesamicol: in vitro and in vivo characterization for vesicular acetylcholine transporter. Synapse. 2000;38:27–37
  29. Bando K, Taguchi K, Ginoza Y, Naganuma T, Tanaka Y, Koike K, et al. Synthesis and evaluation of radiolabeled piperazine derivatives of vesamicol as SPECT agents for cholinergic neurons. Nucl Med Biol. 2001;28:251–260
  30. Efange SM, von Hohenberg K, Khare AB, Tu Z, Mach RH, Parsons SM. Synthesis and biological characterization of stable and radioiodinated (+/−)-trans-2-hydroxy-3-P[4-(3-iodophenyl)piperidyl]-1,2,3,4-tetrahydronaphthalene (3'-IBVM). Nucl Med Biol. 2000;27:749–755
  31. Scheunemann M, Sorger D, Wenzel B, Heinitz K, Schliebs R, Klingner M, et al. Synthesis of novel 4- and 5-substituted benzyl ether derivatives of vesamicol and in vitro evaluation of their binding properties to the vesicular acetylcholine transporter site. Bioorg Med Chem. 2004;12:1459–1465
  32. Shiba K, Ogawa K, Ishiwata K, Yajima K, Mori H. Synthesis and binding affinities of methylvesamicol analogs for the acetylcholine transporter and sigma receptor. Bioorg Med Chem. 2006;14:2620–2626
  33. Wenzel B, Sorger D, Heinitz K, Scheunemann M, Schliebs R, Steinbach J, et al. Structural changes of benzylether derivatives of vesamicol and their influence on the binding selectivity to the vesicular acetylcholine transporter. Eur J Med Chem. 2005;40:1197–1205
  34. Zea-Ponce Y, Mavel S, Assaad T, Kruse SE, Parsons SM, Emond P, et al. Synthesis and in vitro evaluation of new benzovesamicol analogues as potential imaging probes for the vesicular acetylcholine transporter. Bioorg Med Chem. 2005;13:745–753
  35. Scheunemann M, Sorger D, Kouznetsova E, Sabri O, Schliebs R, Wenzel B, et al. Sequential ring-opening of trans-1,4-cyclohaxadiene dioxide for an expedient modular approach to 6,7-disubstituted (±) hexahydro-benzo [1,4]oxazin-3-ones. Tetrahedron Lett. 2007;48:5497–5501
  36. Efange SM, Khare AB, Mach RH, Parsons SM. Hydroxylated decahydroquinolines as ligands for the vesicular acetylcholine transporter: synthesis and biological evaluation. J Med Chem. 1999;42:2862–2869
  37. Rogers GA, Stone-Elander S, Ingvar M, Eriksson L, Parsons SM, Widen L. 18F-labelled vesamicol derivatives: Syntheses and preliminary in vivo small animal Positron Emission Tomography evaluation. Nucl Med Biol. 1994;21:219–230
  38. Cheng YC, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol. 1973;22:3099–3108
  39. Roghani A, Feldman J, Kohan SA, Shirzadi A, Gundersen CB, Brecha N, et al. Molecular cloning of a putative vesicular transporter for acetylcholine. Proc Natl Acad Sci U S A. 1994;91:10620–10624
  40. Huang Y, Hammond PS, Wu L, Mach RH. Synthesis and structure-activity relationships of N-(1-benzylpiperidin-4-yl)arylacetamide analogues as potent sigma1 receptor ligands. J Med Chem. 2001;44:4404–4415
  41. Arvidsson U, Riedl M, Elde R, Meister B. Vesicular acetylcholine transporter (VAChT) protein: a novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J Comp Neurol. 1997;378:454–467
  42. Marshall IG. Studies on the blocking action of 2-(4-phenyl piperidino) cyclohexanol (AH5183). Br J Pharmacol. 1970;38:503–516
  43. Halldin C, Gulyas B, Langer O, Farde L. Brain radioligands — state of the art and new trends. Q J Nucl Med. 2001;45:139–152
  44. Mulholland GK, Wieland DM, Kilbourn MR, Frey KA, Sherman PS, Carey JE, et al. [18F]fluoroethoxy-benzovesamicol, a PET radiotracer for the vesicular acetylcholine transporter and cholinergic synapses. Synapse. 1998;30:263–274
  45. Tu LQ, Wright PF, Rix CJ, Ahokas JT. Is fluoroacetate-specific defluorinase a glutathione S-transferase?. Comp Biochem Physiol C Toxicol Pharmacol. 2006;143:59–66
  46. Johnson JA, el Barbary A, Kornguth SE, Brugge JF, Siegel FL. Glutathione S-transferase isoenzymes in rat brain neurons and glia. J Neurosci. 1993;13:2013–2023

 This work was supported by a grant from Sächsisches Ministerium für Wissenschaft und Kunst, contract no. 7531.50-03-0361-01/6.

PII: S0969-8051(07)00252-1

doi: 10.1016/j.nucmedbio.2007.10.004

Nuclear Medicine and Biology
Volume 35, Issue 2 , Pages 185-195 , February 2008