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Halogenated Benzamides as Ligands for Cerebral Dopamine Receptors

  • Ronald G. Manning
  • N. Scott Mason
  • Tomas de Paulis
  • Robert M. Kessler

Abstract

In the past several years our group has synthesized a series of high affinity iodine-123 and fluorine-18 labeled substituted benzamide ligands for SPECT and PET visualization of the dopamine D-2 receptors in brain regions with low receptor density outside the striatum. Radioiodination and radiofluorination in high yield and high specific activity was achieved by using the tributyltin precursor and nucleophilic displacement of the toluensulfonyl ester precursor, respectively.

Keywords

Allyl Bromide Lithium Aluminum Hydride Tosyl Chloride Basic Hydrogen Peroxide Dimethoxybenzoic 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.

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References

  1. 1.
    Kiesewetter, D.O.; Brucke, T.; Finn, R.D. Radiochemical Synthesis of [18F] Fluororaclopride. Appl. Radiat. Isot. 1989, 40,455–460.CrossRefGoogle Scholar
  2. 2.
    Fukumura, T.; Dohmoto, H.; Maeda, M.; Fukuzawa, E.; Kojima, M. Synthesis and in vitro Affinity for Dopamine D-2 Receptor of N-Fluorine-Substituted Analogs of Eticlopride. Chem.. Pharm. Bull. 1990, 38, 1740–1742.PubMedCrossRefGoogle Scholar
  3. 3.
    Mukherjee, J., Luh, K. E.; Yasillo, N.; Perry B.D.; Levy, D.; Chen, C-T.; Ortega, C., Beck, R. N.; Cooper, M. Dopamine D-2 Receptors Imaged by PET in Cebus apella Using [18F] Benzamide Neuroleptic. Eur J. Pharm. 1990, 175, 363–364.CrossRefGoogle Scholar
  4. 4.
    Mukherjee, J.; Perry, B.D.; Cooper, M. Fluorinated Benzamide Neuroleptics. J Labelled Cmpnds.and Radiopharm. 1990, 28, 609–616.CrossRefGoogle Scholar
  5. 5.
    Kiesewetter, D.O.; Kawai, R.; Chelliah M.; Owens, E.; McLellan, C; Blasberg, R.G. Preparation and Biological Evaluation of 18F-labeled Benzamide Analogs as Potential Dopamine D2 Receptor Ligands. Int. J. Radiat. Appl. Instrum. 1990, 17, 347–356.CrossRefGoogle Scholar
  6. 6.
    Gerdes, J. M.; Bishop, J. E.; Mathis, C. A. Fluoroalkybenzenes: Synthesis of (S)-2.3-Dimethoxy-5-[(3-fluoro)propyl]-6-hydroxy-N-[(l-ethyl-2-pyrrolidinyl) methyl] benzamide. J. Fluorine Chem. 1991, 51, 149–152.CrossRefGoogle Scholar
  7. 7.
    Hall, H.; Hogberg, T.; Halldin, C; Bengtsson, S.; Wedel, I. Synthesis and Binding Properties of the Fluorinated Substituted Benzamide [3H]NCQ 115, a New Selective Dopamine D2 Receptor Ligand. Eur. J. Pharmacol. 1991, 201, 1–10.PubMedCrossRefGoogle Scholar
  8. 8.
    Halldin, C.; Farde L.; Hogberg, T.; Hall, H.; Strom, P.; Ohlberger, A.; Solin, O. A Comparative PET-Study of Five Carbon-11 or Fluorine-18 Labelled Salicylamides. Preparation and In Vitro Dopamine D-2 Receptor Binding. Nucl. Med. Biol. 1991, 18,871–881.Google Scholar
  9. 9.
    Mukherjee, J. Fluorinated Benzamide Neuroleptics—2. Synthesis and Radiosynthesis of (S)-N-[(l-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-3-substituted- 2-methoxy- benzamides. Appl. Radiat. Isot. 1991, 42, 713–721.CrossRefGoogle Scholar
  10. 9.
    Mukherjee, J. Fluorinated Benzamide Neuroleptics—2. Synthesis and Radiosynthesis of (S)-N-[(l-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-3-substituted- 2-methoxy- benzamides. Appl. Radiat. Isot. 1991, 42, 713–721f.CrossRefGoogle Scholar
  11. 11.
    Watanabe, K.; Fukumura, T.; Sasaki, S.; Maeda, M.; Takehara S. New Fluorine- Substituted Analogue of Eticlopride with High Affinity Toward Dopamine D2 Receptors. Chem. Pharm. Bull. 1991, 39, 3211–3214.PubMedCrossRefGoogle Scholar
  12. 12.
    Mathis, C. A.; Bishop, J. E., Gerdes, J. M.; Whitney, J.M., Brennam, K.M., and Jagust, W.J.. Synthesis and Evaluation of High Affinity, Aryl-substituted [18F]Fluoropropylbenzamides for Dopamine D-2 Receptor Studies. Nucl. Med. Biol. 1992, 19,571–588.Google Scholar
  13. 13.
    13. Chumpradit, S.; Kung, M.P.; Billings, J.; Mach R.; Kung. H.F. Fluorinated and Iodinated Dopamine Agents: D2 Imaging Agents for PET and SPECT. J. Med. Chem. 1992.Google Scholar
  14. 14.
    Sasaki, S.; Takao, F.; Watanabe, K.; Obana, N.; Maeda, M.; Fukumura, T.; Takehara, S. New Fluorinated Dopamine D2 Ligands with Benzofuran Skeleton. The Synthesis and in Vitro Evaluation. Chem. Pharm. Bull. 1993, 41, 296–300.PubMedCrossRefGoogle Scholar
  15. 15.
    Kessler, R. M.; Votaw, J. R.; Schmidt, D.E.; Ansari, M.S.; Holdeman, K.P.; de Paulis, T.; Clanton, J.A.; Pfeffer, R.; Manning, R.G.; Ebert, M.H. High Affinity Dopamine D2 Receptor Radioligands. 3. [123I] and [125I]Epidepride: In Vivo Studies in Rhesus Monkey Brain and Comparison with In Vitro Pharmacokinetics in Rat Brain. Life Sciences 1993,53,241–250.PubMedCrossRefGoogle Scholar
  16. 16.
    Kung, H. F.; Kasliwal, R.; Pan, S.; Kung M-P.; Mach, R. H.; Guo, Y-Z. Dopamine D-2 Receptor Imaging Radiopharmaceuticals: Synthesis, Radiolabeling, and in Vitro Binding of (R)-(+)-and (S)-(-)-3-Iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl] benzamide. J. Med. Chem. 1988, 31, 1039–1043.PubMedCrossRefGoogle Scholar
  17. 17.
    de Paulis, T.; Janowsky, A.; Kessler, R.M.; Clanton, J.A.; Smith H.E. (S)-N-[(l- Ethyl- 2-pyrrolidinyl)methyl]-5-[125I]iodo-2-methoxybenzamide Hydrochloride, a New Selective Radioligand for Dopamine D-2 Receptors. J. Med. Chem. 1988, 31,2027–2033.PubMedCrossRefGoogle Scholar
  18. 18.
    Kung, H.F.; Pan, S.; Kung, M-P.; Billings, J.; Kasliwal, R.; Reilley, J.; Alavi, A. In Vitro and In Vivo Evaluation of [123I]IBZM: A Potential CNS D-2 Dopamine Receptor Imaging Agent. J. Nucl. Med. 1989, 30, 88–92.PubMedGoogle Scholar
  19. 19.
    Sanchez-Roa, P.M.; Grigoriadis, D.E.; Wilson, A.A.; Sharkey, J.; Dannais, R.F.; Villemagne, V.L.; Wong, D.F.; Wagner, H.N. Kuhar, M.J.; [125]I-Spectramide: A Novel Benzamide Displaying Potent and Selective Effects at the D2 Dopamine Receptor. Life Sci. 1989,45,1821–1829.PubMedCrossRefGoogle Scholar
  20. 20.
    Hogberg, T.; Strom, P.; Hall, H.; Kohler, G; Halldin, G; Farde, L. Syntheses of [123I]-, [125T]- and Unlabelled (S)-3-iodo-5,6-dimethoxy-N-[l-ethyl-2- pyrrolidinyl) methyl] salicylamide (NCQ 298), Selective Ligands for the Study of Dopamine D-2 Receptors. Acta. Pharm. Nord. 1990, 1, 53–60.Google Scholar
  21. 21.
    Murphy, R.A.; Kung, H.F.; Kung, M-P.; Billings, J. Synthesis and Characterization of Iodobenzamide Analogues: Potential D-2 Dopamine Receptor Imaging Agents. J. Med. Chem. 1990, 33, 171–178.PubMedCrossRefGoogle Scholar
  22. 22.
    Hogberg, T de Paulis, T.; Johansson, L.; Kumar, Y.; Hall, H.; Ogren, S.O..; Potential Antipsychotic Agents. 7. Synthesis and Antidopamingergic Properties of the Atypical Highly Potent (S)-5-Bromo-2,3-dimethoxy-N-[(l-ethyl-2-pyrrolidinyl) methyl]benzamide and Related Compounds. A Comparative Study. J. Med. Chem. 1990, 33, 2305–2309.PubMedCrossRefGoogle Scholar
  23. 23.
    Kessler, R.M.; Ansari, M.S de Paulis, T.; Schmidt, D.E.; Clanton Smith, H.E.; Manning, R.G.; Gillespie, D.; Ebert, M.H..; High Affinity Dopamine D2 Receptor Radioligands. 1. Regional Rat Brain Distribution of Iodinated Benzamides. J. Nucl. Med. 1991, 32, 1593–1600.PubMedGoogle Scholar
  24. 24.
    Clanton, J.A de Paulis, T., Schmidt, D.E., Ansari, M.S.; Manning, R.G.; Baldwin, R.M.; Kessler, R.M..; Preparation of [123I]- and [125I]Epidepride: A Dopamine D-2 Receptor Antagonist Radioligand. J. Label Cmpnd Radiopharma 1991, 29, 745–751.CrossRefGoogle Scholar
  25. 25.
    de Paulis, T.; Bingham, D.R.; Manning, R.G.; Mason, N.S.; Ansari, M.S.; Schmidt, D.E.; Kessler, R. M. Design and Radiogluorination of Benzamide Dopamine D2 Receptor Ligands. New Trends in Radiopharmaceutical Synthesis, Quality Assurance, and Regulatory Control 1991, 97–107.Google Scholar
  26. 26.
    Kessler, R.M.; Ansari, M.S.; Schmidt de Paulis, T.; Clanton, J.A.; Innis, R.; Al- Tikriti, M.; Manning, R.G.; Gillespie, D., D.E.; High Affinity Dopamine D2 Receptor Radioligands. 2. [125I] Epidepride, a Potent and Specific Radioligand for the Characterization of Striatal and Extrastriatal Dopamine D2 Receptors. Life Sci 1991, 49, 617–628.PubMedCrossRefGoogle Scholar
  27. 27.
    Kessler, R.M.; Whetsell, W.O.; Ansari, M.S.; Votaw, J.R de Paulis, T.; Clanton, J.A.; Schmidt, D.E.; Mason, N.S.; Manning, R.G..; Identification of Extrastriatal Dopamine D2 Receptors in Post Mortem Human Brain with [125I]Epidepride. Brain Res. 1993, 609, 237–243.PubMedCrossRefGoogle Scholar
  28. 28.
    Kessler, R.M.; Mason, N.S.; Votaw, J.R de Paulis, T.; Clanton, J.A.; Ansari, M.S.; Schmidt, D.E.; Manning, R.G.; Bell, R.L..; Visualization of Extrastriatal Dopamine D-2 Receptors in the Human Brain. Eur. J. Pharmacol. 1992, 223, 105–107.PubMedCrossRefGoogle Scholar
  29. 29.
    Kessler, R.M.; Votaw, J.R de Paulis, T.; Bingham, D.R.; Ansari, M.S.; Mason, N.S.; Holburn, G.; Schmidt, D.E.; Votaw, D.B.; Manning, R.G.; Ebert, M.H..; Evaluation of 5-[18F]Fluoropropylepidepride as a Potential PET Radioligand for Imaging Dopamine D2 Receptors. Synapse 1993,15,169–176.PubMedCrossRefGoogle Scholar
  30. 30.
    Neve, K.A.; Henningsen, R.A.; Kinzie, J.M de Paulis, T.; Schmidt, D.E.; Kessler, R.M.; Janowsky, A..; Sodium-Dependent Isomerization of Dopamine D-2 Receptors Characterized Using [125I]Epidepride, a High-Affinity Substituted Benzamide Ligand. J. Pharmacol. Exp. Ther. 1990, 252, 1108–1116.PubMedGoogle Scholar
  31. 31.
    Kung, H.F.; Alavi, A.; Chang, W.; Kung, M-P.; Keyes, J.W.; Velchik, M.G.; Billings, J.; Pan, S.; Noto, R.; Rausch, A.; Reilley, J. In Vivo SPECT Imaging of CNS D-2 Dopamine Receptors: Initial Studies with Iodine- 123-IBZM in Humans. J. Nucl. Med. 1990,31,573–579.PubMedGoogle Scholar
  32. 32.
    Kung, M-P.; Kung, H.F.; Billings, J.; Yang, Y.; Murphy, R.; Alavi, A. The Characterization of IBF as a New Selective Dopamine D-2 Receptor Imaging Agent. J. Nucl. Med. 1990, 31,648–654.PubMedGoogle Scholar
  33. 33.
    Brucke, T.; Podreka, I.; Angelberger, P.; Wenger, S.; Topitz, A.; Kufferle, B.; Müller, C; Deecke, L. Dopamine D2 Receptor Imaging with SPECT: Studies in Different Neuropsychiatric Disorders. J. Cereb. Blood Flow Metab 1991, 11, 220–228.PubMedCrossRefGoogle Scholar
  34. 34.
    Verhoeff, N.P.L.G.; Bobeldijk, M.; Feenstra, M.G.P.; Boer, G.J.; Maas, M.A.W.; Erdtsieck-Ernste, E.; De Bruin, K. Van Royen, E.A.; In Vitro and In Vivo D2- Dopamine Receptor Binding with [123I]S(-)iodobenzamide ([123I]IBZM) in Rat and Human Brain. Nucl. Bed. Biol. 1991, 18, 837–846.Google Scholar
  35. 35.
    Joyce, J. N.; Janowsky, A.; Neve, K.A. Characterization and Distribution of [125I]Epidepride Binding to Dopamine D2 Receptors in Basal Ganglia and Cortex of Human Brain. J. Pharmacol. Exp. Ther. 1991, 257, 1253–1263.PubMedGoogle Scholar
  36. 36.
    Innis, R.B.; Malison, R.T.; Al-Tikriti, M.; Hoffer, P.B.; Sybirska, E.H.; Seibyl, J.P.; Zoghbi, S.S.; Baldwin, R.M.; Laruelle, M.; Smith, E.O.; Charney, D.S.; Heninger, G.; Elsworth, J.D.; Roth, R.H. Amphetamine-Stimulated Dopamine Release Competes In Vivo for [123I]ibzM Binding to the D2 Receptor in Nonhuman Primates. Synapse 1992, 10, 177–184.PubMedCrossRefGoogle Scholar
  37. 37.
    Hall, H.; Hogberg, T; Halldin, C; Kohler, C; Strom, P.; Ross, S.B.; Larsson, S.A.; Farde, L. NCQ 298, A New Selective iodinated Salicylamide Ligand for the Labelling of Dopamine-D2 Receptors. Psychopharm. 1991, 103,6.CrossRefGoogle Scholar
  38. 38.
    Votaw, J.R.; Kessler, R.M de Paulis, T.; Ansari, M.S.; Mason, N.S.; Schmidt, D.E., Manning, R.G.; Holburn, G..; Quantification of Striatal and Extra-Striatal Dopamine D2 Receptors Using N-Allyl Fluoropropylepidepride. J. Nucl. Med. 1993, 34, 132 (abst.).Google Scholar
  39. 39.
    Baldwin, R.M.; Al-Tikriti, M.S.; Zea-Ponce, Y.; Zoghbi, S.S.; Sybirska, E.H.; Malison, R.T.; Laruelle, M.; Kung, H.F.; Kessler, R.M de Paulis, T.; Nakatsuka, I.; Saji, H.; Smith, E.O.; Wisniewski, G.; Charney, D.S.; Hoffer, P.B.; Innis, R.B..; In Vivo Comparison of 3 Radioiodinated High Affinity Dopamine D2 Receptor Ligands: IBF, EPID, and 2′-ISP. J. Nucl. Med. 1992, 33, 848 (abst.).Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Ronald G. Manning
    • 1
  • N. Scott Mason
    • 1
  • Tomas de Paulis
    • 1
  • Robert M. Kessler
    • 1
  1. 1.Department of RadiologyVanderbilt University School of MedicineNashvilleUSA

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