, Volume 103, Issue 1, pp 6–18 | Cite as

NCQ 298, a new selective iodinated salicylamide ligand for the labelling of dopamine D2 receptors

  • H. Hall
  • T. Högberg
  • C. Halldin
  • C. Köhler
  • P. Ström
  • S. B. Ross
  • S. A. Larsson
  • L. Farde
Original Investigations


NCQ 298 ((S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylamide) has an iodine substituent. We have labelled NCQ 298 with123I and125I, and used the radioligands as tracers in receptor studies in vitro, in vivo in autoradiography and in SPECT studies on Cynomolgus monkeys.

[125I]NCQ 298 bound in vitro to a single binding site with a KD=19 pM. NCQ 298 has thus a 10-fold higher affinity for the dopamine D2 receptors than the corresponding des-5-methoxy compound FLA 961 (IBZM), previously used in SPECT studies. The binding of [125I]NCQ 298 was entirely reversible (T1/2=17.5 min at 37° C). Autoradiographical studies in vitro on rat and monkey brain tissue sections showed a distinct binding in caudate-putamen, nucleus accumbens, substantia nigra, and in layer 5 of the cerebral cortex. In vivo binding studies in mice showed a ratio of 10 between [125I]NCQ 298 binding in striatum and cerebellum. Binding was displaced by the selective dopamine D2 receptor antagonist raclopride. In SPECT studies with [123I]NCQ 298 in two Cynomolgus monkeys, radioactivity accumulated in the basal ganglia. The measured striatum to cerebellum ratio was about 15 after 3 h. A monkey brain phantom was constructed for the determination of conversion factors from pixel events to actual radioactivity. The resulting, corrected striatum to cerebellum ratio obtained was 30. After administration of 12 mg raclopride to one of the monkeys there was a substantial decrease in striatal radioactivity. [125I]NCQ 298 is a suitable ligand for the labelling of dopamine D2 receptors in vitro and in vivo. The specific properties of [123I]NCQ 298 suggest that this compound is a useful ligand for quantitative SPECT studies of dopamine D2 receptors in man.

Key words

SPECT Dopamine receptors NCQ 298 Iodinated radioligand Salicylamide 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bengtsson S, Högberg T (1989) Secondary β-aminobenzamide and heteroatom directed lithiation in the synthesis of 5,6-dimethoxy-anthranilamides and related compounds. J Org Chem 54:4549–4553Google Scholar
  2. Bengtsson KS, Högberg T, Johansson LG, de Paulis T, Ström HEP, Widman MW, Ögren SO (1985) Oxysalicylamido derivatives. Eur Pat Appl 85850022-6.Google Scholar
  3. Crawley JCW, Crow TJ, Johnstone EC, Oldland SRD, Owen F, Owens DGC, Smith T, Veall N, Zanelli GD (1986) Uptake of77Br-spiperone in the striata of schizophrenic patients and controls. Nucl Med Commun 7:599–607Google Scholar
  4. Ehrin E, Gawell L, Högberg T, de Paulis T, Ström P (1987) Synthesis of methoxy (methoxy-3H)- and (methoxy-11C)-labelled raclopride — specific dopamine-D2 receptor ligands. J Labelled Comp Radiopharm 24:931–939Google Scholar
  5. Farde L, Ehrin E, Eriksson L, Greitz T, Hall H, Hedström CG, Litton JE, Sedvall G (1985) Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA 82:3863–3867Google Scholar
  6. Farde L, Hall H, Ehrin E, Sedvall G (1986) Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231:258–261Google Scholar
  7. Farde L, Pauli S, Hall H, Eriksson L, Halldin C, Högberg T, Nilsson L, Sjögren I, Stone-Elander S (1988a) Stereoselective binding of11C-raclopride binding in living human brain — a search for extrastriatal D2-dopamine receptors by PET. Psychopharmacology 94:471–478Google Scholar
  8. Farde L, Wiesel F-A, Halldin C, Sedvall G (1988b) Central D2-dopamine occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76Google Scholar
  9. Farde L, Eriksson L, Blomquist G, Halldin C (1989) Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET-A comparison to the equilibrium analysis. J Cereb Blood Flow Metab 9:696–708Google Scholar
  10. Gawell L, Hall H, Köhler C (1985) Preparation of tritium labelled benzamide dopamine-D2 ligands at high specific activity. J Labelled Comp Radiopharm 22:1033–1043Google Scholar
  11. Hall H, Sällemark M (1987) Effects of chronic neuroleptic treatment on agonist affinity states of the dopamine-D2 receptors in the rat brain. Pharmacol Toxicol 60:359–363Google Scholar
  12. Hall H, Thor L (1979) Evaluation of a semiautomatic filtration technique for receptor binding studies. Life Sci 24:2293–2300Google Scholar
  13. Hall H, Wedel I (1986) Comparisons between the in vitro binding of two substituted benzamides and two butyrophenones to dopamine-D2 receptors in the rat striatum. Acta Pharmacol Toxicol 58:368–373Google Scholar
  14. Hall H, Högberg T, de Paulis T, Ström P, Ögren S-O (1985a) Catecholcarboxamides. Swedish Pat Appl 8503054-2, and Eur Pat Appl 86850209-7Google Scholar
  15. Hall H, Köhler C, Gawell L (1985b) Some in vitro receptor binding properties of [3H]eticlopride, a novel substituted benzamide, selective for dopamine D2 receptors in the rat brain. Eur J Pharmacol 111:191–199Google Scholar
  16. Hall H, Sällemark M, Jerning E (1986) Effects of remoxipride and some related new substituted salicylamides on rat brain receptors. Acta Pharmacol Toxicol 58:61–70Google Scholar
  17. Hall H, Wedel I, Sällemark M (1988) Effects of temperature on the in vitro binding of3H-raclopride to rat striatal dopamine D2 receptors. Pharmacol Toxicol 63:118–121Google Scholar
  18. Hall H, Högberg T, Halldin C, Köhler C, Ström P (1989) Design and properties of some highly potent benzamides — selective tools for investigation of dopamine D2 receptors. Abstract from symposium on Radio Iodinated Molecules for In Vivo Receptor mapping with SPECT, Brussels, 1989Google Scholar
  19. Hall H, Högberg T, Halldin C, Köhler C, Ross S, Larsson S, Ström P, Farde L (1990a) [123I]-, [125I]- and unlabelled NCQ 298 — selective tools for examination of D-2 dopamine receptors. J Nucl Med 31:796Google Scholar
  20. Hall H, Wedel I, Halldin C, Kopp J, Farde L (1990b) Comparison of the in vitro receptor binding properties of [3H]N-methyl-spiperone and [3H]raclopride to rat and human brain membranes. J Neurochem (in press)Google Scholar
  21. Halldin C, Stone-Elander S, Farde L, Sedvall G (1987) Synthesis of11C-labelled eticlopride, a new selective D2 receptor ligand. J Nucl Med 28:625Google Scholar
  22. Halldin C, Farde L, Högberg T, Hall H, Sedvall G (1990a)11C-Labelling of eticlopride in two different positions — a highly selective high affinity ligand for the study of dopamine D-2 receptor using PET. Appl Radiat Isot 41:669–674Google Scholar
  23. Halldin C, Högberg T, Bengtsson S, Hall H, Farde L (1990b) Preparation of [18F]NCQ 115, a new selective reversible D-2 dopamine receptor ligand for PET. J Nucl Med 31:902Google Scholar
  24. Hill AV (1910) A new mathematical treatment of changes of ionic concentrations in a muscle and nerve under the action of electric currents, with a theory as to their mode of excitation J Physiol 40:190–224Google Scholar
  25. Högberg T, Rämsby S, Ögren SO, Norinder U (1987) New selective dopamine D-2 antagonists as antipsychotic agents. Pharmacological, chemical, structural and theoretical considerations. Acta Pharm Suec 24:289–328Google Scholar
  26. Högberg, T, Bengtsson S, de Paulis T, Johansson L, Ström P, Hall H, Ögren SO (1990a) Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5,6-dimethoxysalicylamides and related compounds. J Med Chem 33:1155–1163Google Scholar
  27. Högberg T, Ström P, Hall H, Köhler C, Halldin C, Farde L (1990b) Synthesis of [123I]-, [125I]-and unlabelled (S)-3-iodo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]salicylamide (NCQ 298), selective ligands for the study of dopamine D-2 receptors. Acta Pharm Nord 2:53–60Google Scholar
  28. Högberg T, Ström P, Hall H, Ögren SO (1990c) Potential antipsychotic agents. 8. Antidopaminergic properties of a potent series of 5-substituted (-)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-dimethoxybenzamides. Synthesis via common lithio intermediates. Helv Chim Acta 73:417–425Google Scholar
  29. Högberg T, de Paulis T, Johansson L, Kumar Y, Hall H, Ögren SO (1990d) Potential antipsychotic agents. 7. Synthesis and antidopaminergic properties of the atypical highly potent (S)-5-bromo-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-benzamide and related compounds. A comparative study. J Med Chem 33:2305–2309Google Scholar
  30. Janowski A, de Paulis T, Clanton JA, Smith HE, Ebert MH, Kessler RM (1988) [125I]Iodopride: a specific high affinity radioligand for labelling striatal dopamine D-2 receptors. Eur J Pharmacol 150:203–205Google Scholar
  31. Kessler RM, de Paulis T, Ansari S, Gillespie D, Clanton JA, Smith HE, Ebert M, Manning R (1989) High affinity substituted benzamides for SPECT. J Nucl Med 30:803Google Scholar
  32. Köhler C, Karlsson-Boethius G (1988) In vivo labelling of rat brain dopamine D-2 receptors. Stereoselective blockade by the D-2 antagonist raclopride and its enantiomer of3H-spiperone,3H-N,N-propylnorapomorphine and3H-raclopride binding in the rat brain. J Neural Transm 73:87–100Google Scholar
  33. Köhler C, Radesäter A-C (1986) Autoradiographic visualization of dopamine D-2 receptors in the monkey brain using the selective benzamide drug (3H)raclopride. Neurosci Lett 66:85–90Google Scholar
  34. Köhler C, Hall H, Ögren SO, Gawell L (1985) Specific in vitro and in vivo binding of3H-raclopride, a potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain. Biochem Pharmacol 34:2251–2259Google Scholar
  35. Kung HF, Billings J, Guo Y-Z, Xu X, Mach RH, Blau M, Ackerhalt RA (1988a) Preparation and biodistribution of [123I]IBZM: a potential CNS D-2 dopamine receptor imaging agent. Nucl Med Biol 15:195–201Google Scholar
  36. Kung HF, Kasliwal R, Pan S, Kung M-P, Mach RH, Guo Y-C (1988b) 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 31:1039–1043Google Scholar
  37. Larsson SA (1980) Gamma camera emission tomography. Development of properties of a multisectional emission computed tomography system. Acta Radiol [Suppl] 363:1–75Google Scholar
  38. Larsson SA, Bergstrand G, Bergstedt H, Berg J, Flygare O, Schnell P-O, Andersson N, Lagergren C (1984) A special cut-off camera for high-resolution SPECT of the head. J Nucl Med 25:1023–1030Google Scholar
  39. Leysen JE, Gommeren W, Laduron PM (1978a) Spiperone, a ligand of choice for neuroleptic receptors. I. Kinetics and characteristics of in vitro binding. Biochem Pharmacol 27:307–316Google Scholar
  40. Leysen JE, Niemeegers CJE, Tollenaere JP, Laduron PM (1978b) Serotonergic component of neuroleptic receptors. Nature 272:168–171Google Scholar
  41. Lidow MS, Goldman-Rakic PS, Rakic P, Innis RB (1989) Dopamine D2 receptors in the cerebral cortex: distribution and pharmacological characterization with [3H]raclopride. Proc Natl Acad Sci USA 86:6412–6416Google Scholar
  42. Maurer AH (1988) Nuclear medicine: SPECT comparisons to PET. Radiol Clin North Am 26:1059–1074Google Scholar
  43. Mizuchi A, Kitagawa N, Saruta S, Miyachi Y (1982) Characteristics of [3H]sultopride binding to rat brain. Eur J Pharmacol 84:51–59Google Scholar
  44. Morgan DC, Marcusson JO, Finch CE (1984) Contamination of serotonin-2 binding sites by an alpha-1 adrenergic component in assays with [3H]spiperone. Life Sci 34:2507–2514Google Scholar
  45. Msaki P, Axelsson B, Dahl CM, Larsson SA (1987) Generalized scatter correction method in SPECT using point scatter distribution functions. J Nucl Med 28:1861–1869Google Scholar
  46. Munson PJ, Rodbard D (1980) Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107:220–239Google Scholar
  47. Nakajima T, Iwata K (1984) [3H]Ro 22-1319 (Piquindone) binds to the D2 dopaminergic receptor subtype in a sodium dependent manner. Mol Pharmacol 26:430–438Google Scholar
  48. Neve KA, Henningsen RA, Kinzie JM, de Paulis T, Schmidt DE, Kessler RM, Janowsky A (1990) Sodium dependent isomerization of dopamine D-2 receptors characterized using [125I]epidepride, a high affinity substituted benzamide ligand. J Pharmacol Exp Ther 252:1108–1116Google Scholar
  49. de Paulis T, Kumar Y, Johansson L, Rämsby S, Florvall L, Hall H, Ängeby-Möller K, ögren SO (1985) Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides. J Med Chem 28:1263–1269Google Scholar
  50. de Paulis T, Kumar Y, Johansson L, Rämsby S, Hall H, Sällemark M, Ängeby-Möller K, Ögren SO (1986) Potential neuroleptic agents. 4. Chemistry, behavioral pharmacology, and inhibition of [3H]spiperone binding of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides. J Med Chem 29:61–69Google Scholar
  51. Ögren SO, Högberg T (1988) Novel dopamine D-2 antagonists for the treatment of schizophrenia. ISI Atlas of Science: Pharmacology 141–147Google Scholar
  52. Ögren SO, Hall H, Köhler C, Magnusson G, Sjöstrand S-E (1986) The selective dopamine D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions. Psychopharmacology 90:287–294Google Scholar
  53. Ross SB, Jackson DM (1989) Kinetic properties of the accumulation of3H-raclopride in the mouse brain in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 340:6–12Google Scholar
  54. Sánchez-Roa PM, Grigoriadis DE, Wilson AA, Sharkey J, Dannals RF, Villemagne VL, Wong DF, Wagner Jr HN, Kuhar MJ (1989)[125]I-Spectramide: a novel benzamide displaying potent and selective effects at the D2 dopamine receptor. Life Sci 45:1821–1829Google Scholar
  55. Sedvall G, Farde L, Persson A, Wiesel F-A (1986) Imaging of neurotransmitter receptors in the living human brain. Arch Gen Psychiatry 43:995–1005Google Scholar
  56. Seeman P (1980) Brain dopamine receptors. Pharmacol Rev 32:229–313Google Scholar
  57. Seeman P (1987) The absolute density of neurotransmitter receptors in the brain. J Pharmacol Methods 17:347–360Google Scholar
  58. Seeman P, Lee T, Chau-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719Google Scholar
  59. Seeman P, Guan H-C, Niznik HB (1989) Endogenous dopamine lowers the dopamine D2 receptor density as measured with [3H]raclopride: implications for positron emission tomography of the human brain. Synapse 3:96–97Google Scholar
  60. Theodorou AE, Crockett M, Jenner P, Marsden CD (1980) Cation regulation differentiates specific binding of [3H]sulpiride and [3H]spiperone to rat striatal preparations. J Pharm Pharmacol 32:441–444Google Scholar
  61. Wagner HN Jr, Burns HD, Dannals RF, Wong DF, Långström B, Duelfer T, Frost JJ, Ravert HT, Links JM, Rosenbloom SB, Lukas SE, Kramer AV, Kuhar MJ (1983) Imaging dopamine receptors in the human brain by positron tomography. Science 221:1264–1266Google Scholar
  62. Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JFW (1988) 1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels σ-type receptors for psychotomimetic opiates and antipsychotic drugs. Proc Natl Acad Sci USA 83:8784–8788Google Scholar
  63. Weiland GA, Molinoff PB (1981) Quantitative analysis of drug receptor interactions: i. Determination of kinetic and equilibrium properties. Life Sci 29:313–330Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • H. Hall
    • 1
    • 2
  • T. Högberg
    • 1
  • C. Halldin
    • 2
  • C. Köhler
    • 1
  • P. Ström
    • 1
  • S. B. Ross
    • 1
  • S. A. Larsson
    • 3
  • L. Farde
    • 2
  1. 1.CNS2 Research and DevelopmentAstra Research Centre ABSödertäljeSweden
  2. 2.Department of Psychiatry and PsychologyKarolinska HospitalStockholmSweden
  3. 3.Department of Radiation PhysicsKarolinska HospitalStockholmSweden

Personalised recommendations