Fluorinated Azabicycloesters as Muscarinic Receptor Ligands for Application with PET

  • Ali M. Emran


Human muscarinic acetylcholine receptors (MAR) play an important role in a number of physiological and behavioral responses (1). A correlation has been established between changes in the MAR density and human memory as well as to other specific neurodegenerative disorders such as Huntington’s chorea or Alzheimer’s dementia (2–9). MAR density has been observed, also, to decrease under the effect of several chemical agents such as organophosphorus compounds (10), barbiturates, ethanol or antidepressants (11). Most of the studies on human MAR were done on post-mortem samples obtained at autopsy and stored for variable times (12–15) which may not reflect the actual in vivo status of such receptors. To carry out preliminary in vivo studies, the choice will be directed primarily to experimental animals. However, animal models for many of the neurodegenerative disorders may be inadequate (16). Several studies showed a dramatically increasing number of dementia cases (17) which is leading to decreased survival among this group (18, 19). Such a dramatic increase in Alzheimer’s dementia cases and the inability to determine the density and distribution of MAR in vivo have stimulated the interest of many researchers to investigate MAR mapping.


Positron Emission Tomography Muscarinic Receptor Muscarinic Acetylcholine Receptor Familial Dysautonomia Tropic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Olsen, R.W., Reisine, T.D., and Yamamura, H.I., Neurotransmitter receptors-biochemistry and alterations in neuropsychiatric disorders, Life Sci. 27: 801 (1980).Google Scholar
  2. 2.
    Hiley, C.R. and Bird, E.D., Decreased muscarinic receptor concentration in post-mortem brain in Huntington’s chorea, Brain Res., 80: 355 (1974).Google Scholar
  3. 3.
    Enna, S.J., Bird, E.D., Bennett, Jr. J.P., Bylund, D.B., Yamamura, H.I., Iversen, L.L., and Snyder, S.H., Changes in neurotransmitter receptors in the brain, N. Engl. J. Med. 294:1305 (1976).Google Scholar
  4. 4.
    Van Woert, M., Myasthenia Gravis, Easton Lambert syndrome and familial dysautonomía, in: “Biology of Cholinergic Function,” A. Goldberg, and I. Hanin, eds., Raven Press, N.Y., pp 567–601 (1976).Google Scholar
  5. 5.
    Weiss, B.L., Foster, F.G., and Kupfer, D.J., Cholinergic involvement in neuropsychiatric syndromes, in: “Biology of Cholinergic Function,” A. Goldberg and I. Hanin, eds., Raven Press, N.Y., pp 603–617 (1976).Google Scholar
  6. 6.
    Silbergeld, E. and Goldberg, A., Hyperactivity, in: “Biology of Cholinergic Function,” Goldberg, A. and Hanin, I., eds., Raven Press, N.Y., pp 619–645 (1976).Google Scholar
  7. 7.
    Heilbronn, E. and Bartfai, T., Muscarinic acetylcholine receptor, Prog. Neurobiol. 11:171 (1978).Google Scholar
  8. 8.
    Bartus, R.T., Dean, III, R.L., Beer, B., and Lippa, A.S., The cholinergic hypothesis of geriatric memory dysfunction, Science 217: 408 (1982).Google Scholar
  9. 9.
    Westlind, A., Grynfarb, M., Hedlund, B., Bartfai, T., and Fuxe, K., Muscarinic supersensitivity induced by septal lesion or chronic atropine treatment, Brain Res. 225: 131 (1981).PubMedGoogle Scholar
  10. 10.
    Costa, L.G., Schwab, B.W., and Murphy, S.D., Differential alterations of cholinergic muscarinic receptors during chronic and acute tolerance to organophosphorus insecticides, Biochem. Pharmacol. 31:3407 (1982).Google Scholar
  11. 11.
    Tollefson, G.D., Senogles, S.E., Frey, II W.H., Tuason, V.B., and Nicol, S.E., A comparison of peripheral and central human muscarinic cholinergic receptor affinities for psychotropic drugs, Biol. Psychia. 17:555 (1982).Google Scholar
  12. 12.
    Mash, D.C., Flynn, D.D., and Potter, L.T., Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer’s disease and experimental cholinergic denervation, Science 228: 1115 (1985).Google Scholar
  13. 13.
    Perry, E.K., Perry, R.H., Blessed, G., and Tomlinson, B.E., Necropsy evidence of central cholinergic deficits in senile dementia, Lancet 1: 189 (1977).Google Scholar
  14. 14.
    Reisine, T.D., Yamamura, H.I., Bird, E.D., Spokes, E., and Enna, S.J., Pre-and postsynaptic neurochemical alterations in Alzheimer’s disease, Brain Res., 159: 477 (1978).Google Scholar
  15. 15.
    Bowen, D.M., Allen, S.J., Benton, J.S., Goodhardt, M.J., Haan, E.A., Palmer, A.M., Sims, N.R., Smith, C.C.T., Spillane, J.A., Esiri, M.M., Neary, D., Snowdon, J.S., Wilcock, G.K., and Davison, A.N., Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer’s disease, J. Neurochem. 41:266 (1983).Google Scholar
  16. 16.
    Gibson, R.E., Quantitative changes in receptor concentrations as a function of disease, in: “Receptor-Binding Radiotracers,” W.C. Eckelman, ed., CRC Press, Inc., Boca Raton, pp 185–212 (1982).Google Scholar
  17. 17.
    Davies, P., Neurotransmitter-related enzymes in senile dementia of the Alzheimer type, Brain Res. 171: 319 (1979).Google Scholar
  18. 18.
    Caulfield, M.P., Straughan, D.W., Cross, A.J., Crow, T., and Birdsall, N.J.M., Cortical muscarinic receptor subtypes and Alzheimer’s disease, Lancet 1277 (1982).Google Scholar
  19. 19.
    Katzman, R., The prevalence and malignancy of Alzheimer disease, a major killer, Arch. Neurol. 33:217–218 (1976).Google Scholar
  20. 20.
    Maziere, M., Berger, G., and Comar, D., 11C-radiopharmaceuticals for brain receptor studies in conjunction with positron emission tomography, in: “Applications of Nuclear and Radiochemistry,” Lambrecht and Morcos, eds., Pergamon Press, N.Y., pp 251–270 (1982).Google Scholar
  21. 21.
    Grubb, R.L., Raichle, M.E., Gado, M.H., Eiehling, J.0., and Hughes, C.P., Cerebral blood flow, oxygen utilization and blood volume in dementia, Neurology 27: 905 (1977).Google Scholar
  22. 22.
    Comar, D., Maziere, M., Godot, J.M., Berger, G., and Soussaline, F., Visualisation of 11C-flunitrazepam displacement in the brain of the live baboon, Nature 280: 329 (1979).Google Scholar
  23. 23.
    Maziere, M., Berger, G., Godot, J.M., Prenant, C., and Comar, D., Etorphine 11C: A new tool for “in vivo” study of brain opiate receptors, J. Lab. Compds. Radiopharm. 18:15 (1981).Google Scholar
  24. 24.
    Greenberg, J.H., Reivich, M., Alavi, A., Hand, P, Rosenquist, A., Rintelmann W., Stein, A., Tusa, R., Dann, R., Christman, D., Fowler, J., MacGregor, B., and Wolf, A., Metabolic mapping of functional activity in human subjects with [18F] fluorodeoxyglucose technique, Science 212: 678 (1981).Google Scholar
  25. 25.
    Wilder, B.J., Ramsay, R.E., Murphy, J.V., Karas, B.J., Marquardt, K., and Hammond, E.J., Comparison of valproic acid and phenytoin in newly diagnosed tonic-clonic seizures, Neurology 33: 1474 (1983).Google Scholar
  26. 26.
    Garnett, E.S., Firnau, G., and Nahmias, C., Dopamine visualized in the basal ganglia of living man, Nature 305: 137 (1983).Google Scholar
  27. 27.
    Mintun, M.A., Wooten, D.F., and Raichle, M.E., A quantitative model for the in vivo assessment of drug-binding sites with positron emission tomography, J. Cereb. Blood Flow Metab. 3:S566 (1983).Google Scholar
  28. 28.
    Celesia, G., Polcyn, R., Holden, J., Nickles, R., Koeppe, R., and Gatley, S., 18F-Fluoromethane positron emission tomography determination of regional cerebral blood flow in cerebral infarction, J. Cereb. Blood Flow Metab. 3:S23 (1983).Google Scholar
  29. 29.
    Rottenberg, D.A., Ginos, J.Z., Kearfott, K.J., Junck, L.R., and Dhawan, V., Determination of regional cerebral acid-base status using 11C-dimethyl-oxazolidinedione and dynamic positron emission tomography, J. Cereb. Blood Flow Metab. 3:S150 (1983).Google Scholar
  30. 30.
    Buchsbaum, M.S., Holcomb, H.H., Johnson, J., King, A.C., and Kessler, R., Cerebral metabolic consequences of electrical cutaneous stimulation in normal individuals, Human Neurobiol. 2: 35 (1983).Google Scholar
  31. 31.
    Bustany, P., Henry, J.F., de Rotrou, J., Signoret, J.L., Ziegler, M., Zarifian, E., Soussaline, F., and Comar, D., Local cerebral metabolic rate of 11C-L-methionine in early stages of dementia, schizophrenia, Parkinson’s disease, J. Cereb. Blood Flow Metab. 3:S492 (1983).Google Scholar
  32. 32.
    Emran, A.M., Boothe, T.E., Finn, R.D., Vora, M.M., and Kothari, P.J., Synthesis of high specific activity [11C] labelled 5,5diphenylhydantoin (DPH), in: Proceedings of the 187th ACS National Meeting, Washington, D.C., August 1983.Google Scholar
  33. 33.
    Frost, J.J., Dannals, R.F., Duelfer, T., Burns, H.D., Ravert, H.T., Langstrom, B., Balasubramanian, V., and Wagner, Jr., H.N., In vivo studies of opiate receptors, Ann. Neurol. 15:S85 (1984).Google Scholar
  34. 34.
    Pfeiffer, C.C., Nature and spatial relationship of the prosthetic chemical groups required for maximum muscarinic action, Science 107: 94 (1948).Google Scholar
  35. 35.
    Schueler, F.W., The statistical nature of the intramolecular distance factor of the muscarinic moiety, Arch. Int. Pharmacodyn. 93:417 (1953).Google Scholar
  36. 36.
    Abood, L.G., Biel, J.H., and Ostfeld, A.M., The Psychotogenic effects of some N-substituted piperidyl benzilates, in: “Neuro-Psychopharmacology,” P. Bradley, ed., Pergamon Press, N.Y. p 433 (1959).Google Scholar
  37. 37.
    Triggle, D.J., Structure-activity relationships: chemical constitution and biological activity in: “Chemical Pharmacology of the Synapse,” D.J. Triggle and C.R. Triggle, eds., Academic Press, N.Y., pp 233–430 (1976).Google Scholar
  38. 38.
    Snyder, S.H. and Bennett, Jr., J.P., Neurotransmitter receptors in the brain: biochemical identification, Ann. Rev. Physiol. 38:153 (1976).Google Scholar
  39. 39.
    Aronstam, R.S., Triggle, D.J., and Eldefrawi, M.E., Structure and stereochemical requirements for muscarinic receptor, Mol. Pharm. 15:227 (1974).Google Scholar
  40. 40.
    Abood, L.G. and Biel, J.H., Anticholinergic psychotomimetic agents, Int. Rev. Neurobiol. 4:217 (1962).Google Scholar
  41. 41.
    Burgen, A.S.V., Hiley, C.R., and Young, J.M., The binding of [3H]propylbenzilylcholine mustard by longitudinal muscle strips from guinea-pig small intestine, Br. J. Pharmac. 50:145 (1974).Google Scholar
  42. 42.
    Maayani, S., Weinstein, H., Cohen, S., and Sokolovsky, M., Acetylcholine-like molecular arrangement in psychomimetic anticholinergic drugs, Proc. Nat. Acad. Sci. 70:3101 (1973).Google Scholar
  43. 43.
    Farrow, J.T. and O’Brien, R.D., Binding of atropine and muscarone to 2rat brain fractions and its relation to the acetylcholine receptor, Mol. Pharm., 9: 33 (1973).Google Scholar
  44. 44.
    Beld, A.J. and Ariens, A.J., Stereospecific binding as a tool in attempts to localize and isolate muscarinic receptors: Part II. Binding of (+)benzetimide, (-)benzetimide and atropine to a fraction from bovine tracheal smooth muscle and to bovine caudate nucleus, Europ. J. Pharm. 25:203 (1974).Google Scholar
  45. 45.
    Birdsall, N.J.M., Burgen, A.S.V., Hiley, C.R., and Hulme, E.C., Binding of agonists and antagonists to muscarinic receptors, J. Supramol. Struc. 4:367 (1976).Google Scholar
  46. 46.
    Yamamura, H.I. and Snyder, S.H., Muscarinic cholinergic receptor binding in the longitudinal muscle of the Guinea pig ileum with [3H]-quinculidinyl-benzilate, Mol. Pharm. 10:861 (1974).Google Scholar
  47. 47.
    Repke, H. and Matthies, H., Synthese von Affinitatsgelen zur Isolierung des muscarinergen Acetycholinrezeptors, Z. Chem. 20:60 (1980).Google Scholar
  48. 48.
    Vora, M.M., Finn, R.D., and Boothe, T.E., [N-methyl-11C]-scopolamine: synthesis and distribution in rat brain, J. Lab. Compds. Radiopharm. 20:1229 (1983).Google Scholar
  49. 49.
    Yamamura, H.I., Kuhar, M.J., Greenberg, D., and Snyder, S.H., Muscarinic cholinergic receptor binding: regional distribution in monkey brain, Brain Res., 66: 541 (1974).Google Scholar
  50. 50.
    Yamamura, H.I. and Snyder, S.H., Muscarinic cholinergic binding in rat brain, Proc. Nat. Acad. Sci. 71:1725 (1974).Google Scholar
  51. 51.
    Flynn, D.D. and Potter, L.T., Effect of solubilization on the distinct binding properties of muscarine receptors from rabbit hippocampus and brainstem, Mol. Pharm. 30:193 (1986).Google Scholar
  52. 52.
    Gibson, R.E., Weckstein, D.J., Jagoda, E.M., Rzeszotarski, W.J., Reba, R.C., and Eckelman W.C., The characteristics of I-125 4-IQNB and H-3 QNB in vivo and in vitro, J. Nucl Med. 25:214 (1984).Google Scholar
  53. 53.
    Eckelman, W.C., Eng, R., Rzeszotarski, W.J., Gibson, R.E., Francis, B., and Reba, R.C., Use of 3-quinuclidinyl 4-iodobenzilate as a receptor binding radiotracer, J Nucl. Med. 26:637 (1985).Google Scholar
  54. 54.
    Dannals, R.F., Langstrom, B., Frost, J.J., Ravert, H.T., Wilson, A.A., and Wagner, Jr., H.N., Synthesis of radiotracers for studying muscarinic cholinergic receptors in the living human brain using positron emission tomography: [11C]dexetimide and [11C]levetimide, in: Proceedings of 6th Internat. Symp. on Radiopharm. Chem., MIT, Boston, MA, June 29-July 3, 1986.Google Scholar
  55. 55.
    Mulholland, G.K., Otto, C.A., Jewett, D.M., Kilbourn, M.R., Sherman, P.S., Koeppe, R.A., Wieland, D.M., Frey, K.A., and Kuhl, D.E., Synthesis and preliminary evaluation of [C-11]-(+)-2-tropanyl benzilate (C-11 TRB) as a ligand for the muscarinic receptor, J. Nucl. Med. 29:932 (1988).Google Scholar
  56. 56.
    Vlek, J.W., Feitsma, K.G., van der Mark, T.W., Drenth, B., Paans, A., and Vaalburg, W., Synthesis of d-[11C]oxyphenonium iodide, a potential radioligand for in vivo visualization of human cholinergic muscarinic receptor-sites by positron emission tomography, Appl. Radiat. Isot. 41:453 (1990).Google Scholar
  57. 57.
    Dewey, S.L., MacGregor, R.R., Brodie, J.D., Bendriem, B., King, P.T., Volkow, N.D., Schlyer, D.J., Fowler, J.S., Wolf, A.P., Gatley, S.J., and Hitzemann, R., Mapping muscarinic receptors in human and baboon brain using [N-11C-methyl]-benztropine, Synapse 5: 213 (1990).Google Scholar
  58. 58.
    Lederer, C.M., Hollander, J.N., Perlman, I., Table of Isotopes, John Wiley and Sons, New York, (1986).Google Scholar
  59. 59.
    Eckelman, W.C., Reba, R.C., Rzeszotarski, W.J., Gibson, R.E., Hill, T., Holman, B.L., Budinger, T., Conklin, J.J., Eng, R., Grissom, M.P., External imaging of cerebral muscarinic acetylcholine receptors, Science 223: 291–293 (1984).Google Scholar
  60. 60.
    Emran, A.M., Boothe, T.E., Finn, R.D., Vora, M.M., and Kothari, P.J., Use of 11C as a tracer for studying the synthesis of radio-labelled compounds. II: 2[11C], 5,5-diphenylhydantoin from [11C] cyanide, Int. J. Appl. Radiat. Isot. 37:1033 (1986).Google Scholar
  61. 61.
    Emran, A.M., Boothe, T.E., Finn, R.D., Vora, M.M., Kothari, P.J., Use of liquid chromatography for separation and determination of carrier species associated with the synthesis of no carrier-added 11C- labelled compounds, J. Radioanal. Nucl. Chem. 91:277 (1985).Google Scholar
  62. 62.
    Gibson, R.E., Eckelman, W.C., Vieras, F., Reba, R.C., The distribution of the muscarinic acetylcholine receptor antagonists, quinuclidinyl benzilate and quinuclidinyl benzilate methiodide (both tritiated), in rat, guinea pig, and rabbit, J. Nucl. Med. 20:865 (1974).Google Scholar
  63. 63.
    Prenant, C., Barre, L., and Crouzel, C., Synthesis of [11C]-3quinuclidinylbenzilate (QNB), J. Lab. Compds. Radiopharm. XXVII (11), 1257 (1989).Google Scholar
  64. 64.
    Otto, C.A., Mulholland, G.K., Perry, S.E., Combs, R., Sherman, P.S., and Fisher, S.K., In vitro and ex vivo evaluation of potential pet agents for mAChR, J. Nucl. Med. 29:933 (1988).Google Scholar
  65. 65.
    Emran, A.M., “Radiofluorination of aromatic acids for application in receptor studies”, in: Proceedings of the 199th ACS National Meeting, Boston, MA, April 1990.Google Scholar
  66. 66.
    Wallach, von 0., Beitrage zur Kenntnils der Azo-und Disazoverbindungen, Ann. Chem. 234:242 (1888).Google Scholar
  67. 67.
    Katzenellenbogen, J.A., Carlson, K.E., Heiman, D.F., and Goswami, R., Receptor-binding radiopharmaceuticals for imaging breast tumors: estrogen-receptor interactions and selectivity of tissue uptake of halogenated estrogen, J. Nucl. Med. 21:550 (1980).Google Scholar
  68. 68.
    Yang, D., Emran, A., Tansey, W., Tilbury, R., Kasi, L., Wright, K., Kuang, L., Wallace, S., and Kim, E., Radiosynthesis of fluorotamoxifen analogs, J. Nucl. Med. 31:5 (1990).Google Scholar
  69. 69.
    Emran, A.M., work in progress.Google Scholar
  70. 70.
    Emran, A.M., Lim, J.-L., Flynn, D.D., and Shanbaky, N.M., “Synthesis and evaluation of muscarinic receptor ligands,” unpublished data.Google Scholar
  71. 71.
    Rzeszotarski, W.J., Gibson, R.E., Eckelman, W.C., Simms, D.A., Jagoda, E.M., Ferreira, N.L., and Reba, R.C., Analogues of 3quinuclidinyl benzilate, J. Med. Chem. 25:1103 (1982).Google Scholar
  72. 72.
    Nozaki, T. and Tanaka, Y., The preparation of 18F-labelled aryl fluorides, Int. J. Appl. Radiat. Isot. 18:111 (1967).Google Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Ali M. Emran
    • 1
  1. 1.Cyclotron Facility Positron Diagnostic and Research CenterThe University of Texas Health Science CenterHoustonUSA

Personalised recommendations