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Further characterization of a CNS adenosine A2a receptor ligand [11C]KF18446 within vitro autoradiography andin vivo tissue uptake

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Abstract

PET assessment of the adenosine A2a receptors localized in the striatum offers us a potential new diagnostic tool for neurological disorders. In the present study, we carried outin vitro receptor autoradiography of a newly developed PET ligand [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) with rat brain sections. [11C]KF18446 showed a high striatum/cortex binding ratio (5.0) and low nonspecific binding (<10%), suggesting that [11C]KF18446 has characteristics comparable or slightly superior to [3H]CGS 21680 or [3H]SCH 58261, which are currently available representative A2a receptor ligands. Scatchard analysis indicated a Kd of 9.8 nM and a Bmax of 170 fmol/mm3 tissue in the striatum and a Kd of 16.4 nM and a Bmax of 33 fmol/mm3 tissue in the cortex. Seven xanthine-type and four nonxanthine-type adenosine receptor ligands with an affinity for the adenosine A2a receptors significantly reduced thein vitro binding of [11C]KF18446 to the brain section. The blocking effects were much stronger in the striatum than in the cortex, but did not necessarily parallel their affinity. On the other hand, four xanthine-type ligands and one nonxanthine-type ligand (SCH 58261) of the 11 ligands studied reduced thein vivo uptake of [11C]KF18446 in mice, but other ligands, including A1-selective and nonselective ligands and three nonxanthine-type A2a-selective antagonists did not. We conclude that [11C]KF18446 is a promising adenosine A2a receptor ligand for PET study.

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References

  1. Fredholm BB, Abbracchio MP, Burnstock G, Daly JW, Harden TK, Jacobson KA, et al. Nomenclature and classification of purinoceptors.Pharmacol Rev 46: 143–156, 1994.

    PubMed  CAS  Google Scholar 

  2. Palmer TM, Stiles GL. Adenosine receptors.Neuropharmacology 34: 683–694, 1995.

    Article  PubMed  CAS  Google Scholar 

  3. Ongini E, Fredholm BB. Pharmacology of adenosine A2A receptors.Trends Pharmacol Sci 17: 364–372, 1996.

    Article  PubMed  CAS  Google Scholar 

  4. Lewis ME, Patel J, Edley SM, Marangos PJ. Autoradiographic visualization of rat brain adenosine receptors usingN 6-cyclohexyl[3H]adenosine.Eur J Pharmacol 73: 109–110, 1981.

    Article  PubMed  CAS  Google Scholar 

  5. Goodman RR, Snyder SH. Autoradiographic localization of adenosine receptors in rat brain using [3H]cyclohexyl-adenosine.J Neurosci 2: 1230–1241, 1982.

    PubMed  CAS  Google Scholar 

  6. Fastbom J, Pazos A, Palacios JM. The distribution of adenosine A1 receptors and 5′-nucleotidase in the brain of some commonly used experimental animals.Neuroscience 22: 813–826, 1987.

    Article  PubMed  CAS  Google Scholar 

  7. Pagonopoulou O, Angelatou F, Kostopoulos G. Effect of pentylentetrazol-induced seizures on A1 adenosine receptor regional density in the mouse brain: a quantitative autoradiographic study.Neuroscience 56: 711–716, 1993.

    Article  PubMed  CAS  Google Scholar 

  8. Fastbom J, Pazos A, Probst A, Palacios JM. Adenosine A1 receptors in the human brain: a quantitative autoradiographic study.Neuroscience 22: 827–839, 1987.

    Article  PubMed  CAS  Google Scholar 

  9. Svenningsson P, Hall H, Sedvall G, Fredholm BB. Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study.Synapse 27: 322–335, 1997.

    Article  PubMed  CAS  Google Scholar 

  10. Bruns RF, Lu GH, Pugsley TA. Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes.Mol Pharmacol 29: 331–346, 1986.

    PubMed  CAS  Google Scholar 

  11. Jarvis MF, Williams M. Direct autoradiographic localization of adenosine A2 receptors in the rat brain using the A2-selective agonist, [3H]-CGS 21680.Eur J Pharmacol 168: 243–246, 1989.

    Article  PubMed  CAS  Google Scholar 

  12. Parkinson FE, Fredholm BB. Autoradiographic evidence for G-protein coupled A2-receptors in rat neostriatum using [3H]-CGS21680 as a ligand.Naunyn Schmiedebergs Arch Pharmacol 342: 85–89, 1990.

    Article  PubMed  CAS  Google Scholar 

  13. Johansson B, Georgiev V, Parkinson FE, Fredholm BB. The binding of the adenosine A2 receptor selective agonist [3H]CGS 21680 to rat cortex differs from its binding to rat striatum.Eur J Pharmacol 247: 103–110, 1993.

    Article  PubMed  CAS  Google Scholar 

  14. Cunha RA, Johansson B, van der Ploeg I, Sebastião AM, Ribeiro JA, Fredholm BB. Evidence for functionally important adenosine A2A receptors in the rat hippocampus.Brain Res 649: 208–216, 1994.

    Article  PubMed  CAS  Google Scholar 

  15. Cunha RA, Johansson B, Constantino MD, Sebastião AM, Fredholm BB. Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H]CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors.Naunyn Schmiedebergs Arch Pharmacol 353: 261–271, 1996.

    Article  PubMed  CAS  Google Scholar 

  16. Kirk IP, Richardson PJ. Further characterization of [3H]CGS 21680 binding sites in the rat striatum and cortex.Br J Pharmacol 114: 537–543, 1995.

    PubMed  CAS  Google Scholar 

  17. Johansson B, Fredholm BB. Further characterization of the binding of the adenosine receptor agonist [3H]CGS 21680 to rat brain using autoradiography.Neuropharmacology 34: 393–403, 1995.

    Article  PubMed  CAS  Google Scholar 

  18. Schiffmann SN, Libert F, Vassart F, Vanderhaeghen JJ. Distribution of adenosine A2 receptor mRNA in the human brain.Neurosci Lett 130: 177–181, 1991.

    Article  PubMed  CAS  Google Scholar 

  19. Pollack AE, Harrison MB, Wooten GF, Fink JS. Differential localization of A2a adenosine receptor mRNA with D1 and D2 dopamine receptor mRNA in striatal output pathways following a selective lesion of striatonigral neurons.Brain Res 631: 161–166, 1993.

    Article  PubMed  CAS  Google Scholar 

  20. Martinez-Mir MI, Probst A, Palacios JM. Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease.Neuroscience 42: 697–706, 1991.

    Article  PubMed  CAS  Google Scholar 

  21. Mally J, Stone TW. Potential role of adenosine antagonist therapy in pathological tremor disorders.Pharmacol Ther 72: 243–250, 1996.

    Article  PubMed  CAS  Google Scholar 

  22. Guieu R, Couraud F, Pouget J, Sampieri F, Bechis G, Rochat H. Adenosine and the nervous system: clinical implications.Clin Neuropharmacology 19: 459–474, 1996.

    Article  CAS  Google Scholar 

  23. Ferré S. Adenosine-dopamine interactions in the ventral striatum. Implications for the treatment of schizophrenia.Psychopharmacology (Berl) 133: 107–120, 1997.

    Article  Google Scholar 

  24. Baldessarini RJ. Drugs and the treatment of psychiatric disorders.In Pharmacological Bases of Therapeuitics (Eds. Goodman GA, Rall TW, Nies AS, Taylor P) Pergamon, New York, pp. 383–435, 1990.

    Google Scholar 

  25. Ferré S, O'Connor WT, Snaprud P, Ungerstedt U, Fuxe K. Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia.Neuroscience 63: 765–773, 1994.

    Article  PubMed  Google Scholar 

  26. Shimada J, Suzuki F, Nonaka H, Ishii A, Ichikawa S.(E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl) xanthines: potent and selective adenosine A2 antagonists.J Med Chem 35: 2342–2345, 1992.

    Article  PubMed  CAS  Google Scholar 

  27. Baraldi PG, Cacciari B, Spalluto G, Borioni A, Viziano M, Dionisotti S, et al. Current development of A2a adenosine receptor antagonists.Current Med Chem 2: 707–722, 1995.

    CAS  Google Scholar 

  28. Müller CE, Stein B. Adenosine receptor antagonists: structures and potential therapeutic applications.Current Pharmaceut Design 2: 501–530, 1996.

    Google Scholar 

  29. Poulsen SA, Quinn RJ. Adenosine receptors: new opportunities for future drugs.Bioorg Med Chem 6: 619–641, 1998.

    Article  PubMed  CAS  Google Scholar 

  30. Zocchi C, Ongini E, Conti A, Monopoli A, Negretti A, Baraldi, PG, et al. The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2A adenosine receptor antagonist.J Pharmacol Exp Ther 276: 398–404, 1996.

    PubMed  CAS  Google Scholar 

  31. Poucher SM, Keddie JR, Singh P, Stoggall SM, Caulkett PW, Jones G, et al. Thein vitro pharmacology of ZM 241385, a potent, non-xanthine, A2a selective adenosine receptor antagonist.Br J Pharmacol 115: 1096–1102, 1995.

    PubMed  CAS  Google Scholar 

  32. Palmer TM, Poucher SM, Jacobson KA, Stiles GL.125I-4-(2-[7-amino-2-{2-furyl} {1,2,4} triazolo {2,3-a} {1,3,5} triazin-5-yl-amino]ethyl)phenol, a high affinity antagonist radioligand selective for the A2a adenosine receptor.Mol Pharmacol 48: 970–974, 1995.

    PubMed  CAS  Google Scholar 

  33. Zocchi C, Ongini E, Ferrara S, Baraldi PG, Dionisotti S. Binding of the radioligand [3H]-SCH 58261, a new non-xanthine A2A adenosine receptor antagonist, to rat striatal membranes.Br J Pharmacol 117: 1381–1386, 1996.

    PubMed  CAS  Google Scholar 

  34. Fredholm BB, Lindström K, Dionisotti S, Ongini E. [3H]SCH 58261, a selective adenosine A2A receptor antagonist, is a useful ligand in autoradiographic studies.J Neurochem 70: 1210–1216, 1998.

    Article  PubMed  CAS  Google Scholar 

  35. Ishiwata K, Noguchi J, Toyama H, Sakiyama Y, Koike N, Ishii S, et al. Synthesis and preliminary evaluation of [11C]KF17837, a selective adenosine A2A antagonist.Appl Radiat Isot 47: 507–511, 1996.

    Article  PubMed  CAS  Google Scholar 

  36. Noguchi J, Ishiwata K, Wakabayashi S, Nariai T, Shumiya S, Ishii S, et al. Evaluation of carbon-11 labeled KF17837: a potential CNS adenosine A2a receptor ligand.J Nucl Med 39: 498–503, 1998.

    PubMed  CAS  Google Scholar 

  37. Ishiwata K, Noguchi N, Sakiyama Y, Shimada J, Ishii S, Sakiyama T, et al. Synthesis andin vivo evaluation of11C-labeled xanthine derivatives as a PET tracer for mapping CNS and peripheral adenosine A2a receptors. The 12th International Symposium on Radiopharmaceutical Chemistry held in June 15–19, 1997, in Uppsala, Sweden.

  38. Ishiwata K, Noguchi N, Wakabayashi S, Shimada J, Ogi N, Nariai T, et al. Carbon-11 labeled KF18446: a potential CNS adenosine A2a receptor ligand.J Nucl Med 41: 345–354, 2000.

    PubMed  CAS  Google Scholar 

  39. Suzuki F, Ishiwata K. Selective adenosine antagonists for mapping central nervous system adenosine receptors with positron emission tomography: Carbon-11 labeled KF15372 (A1) and KF17837 (A2a).Drug Develop Res 45: 312–323, 1998.

    Article  CAS  Google Scholar 

  40. Jacobson KA, Nikodijevic O, Padgett WL, Gallo-Rodriguez C, Maillard M, Daly JW. 8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine antagonistin vitro andin vivo.FEBS Lett 323: 141–144, 1993.

    Article  PubMed  CAS  Google Scholar 

  41. Sarges R, Howard HR, Browne RG, Lebel LA, Seymour PA, Koe BK. 4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants.J Med Chem 33: 2240–2254, 1990.

    Article  PubMed  CAS  Google Scholar 

  42. Suzuki F, Shimada J, Mizumoto H, Karasawa A, Kubo K, Nonaka H, et al. Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.J Med Chem 35: 3066–3075, 1992.

    Article  PubMed  CAS  Google Scholar 

  43. Müller CE, Geis U, Hipp J, Schobert U, Frobenius W, Pawlowski M, et al. Synthesis and structure-activity relationships of 3,7-dimethyl-1-propargylxanthine derivatives, A2A-selective adenosine receptor antagonists.J Med Chem 40: 3496–4405, 1997.

    Google Scholar 

  44. Ishiwata K, Ogi N, Tanaka A, Senda M. Quantitativeex vivo andin vitro receptor autoradiography using11C-labeled ligands and an imaging plate: a study with a dopamine-D2 like receptor ligand [11C]nemonapride.Nucl Med Biol 26: 291–296, 1999.

    Article  PubMed  CAS  Google Scholar 

  45. Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, et al. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine.Neuroscience 67: 631–647, 1995.

    Article  PubMed  CAS  Google Scholar 

  46. Nonaka Y, Shimada J, Nonaka H, Koike N, Aoki N, Kobayashi H, et al. Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine.J Med Chem 36: 3731–3733, 1993.

    Article  PubMed  CAS  Google Scholar 

  47. Nonaka H, Ichimura M, Takeda M, Nonaka Y, Shimada J, Suzuki F, et al. KF17837 ((E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine), a potent and selective adenosine A2 receptor antagonist.Eur J Pharmacol 267: 335–341, 1994.

    Article  PubMed  CAS  Google Scholar 

  48. Leo AJ. Calculating logP oct from structures.Chem Rev 93: 1281–1308, 1993.

    Article  CAS  Google Scholar 

  49. Lindström K, Ongini E, Fredholm BB. The selective adenosine A2A receptor antagonist SCH 58261 discriminates between two different binding sites for [3H]-CGS 21680 in the rat brain.Naunyn Schmiedsbergs Arch Pharmacol 354: 539–541, 1996.

    Article  Google Scholar 

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Authors and Affiliations

  1. Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 1-1 Naka-cho, Itabashi, 173-0022, Tokyo, Japan

    Kiichi Ishiwata, Nobuo Ogi & Michio Senda

  2. Showa College of Pharmaceutical Sciences, 1-1 Naka-cho, Itabashi, 173-0022, Tokyo, Japan

    Nobuo Ogi & Akira Tanaka

  3. Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, 1-1 Naka-cho, Itabashi, 173-0022, Tokyo, Japan

    Junichi Shimada, Hiromi Nonaka & Fumio Suzuki

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  1. Kiichi Ishiwata
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  2. Nobuo Ogi
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Correspondence to Kiichi Ishiwata.

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Ishiwata, K., Ogi, N., Shimada, J. et al. Further characterization of a CNS adenosine A2a receptor ligand [11C]KF18446 within vitro autoradiography andin vivo tissue uptake. Ann Nucl Med 14, 81–89 (2000). https://doi.org/10.1007/BF02988585

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  • DOI: https://doi.org/10.1007/BF02988585

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