Annals of Nuclear Medicine

, Volume 17, Issue 3, pp 205–211 | Cite as

Preclinical studies on [11C]TMSX for mapping adenosine A2A receptors by positron emission tomography

  • Kiichi Ishiwata
  • Wei-Fang Wang
  • Yuichi Kimura
  • Kazunori Kawamura
  • Kenji Ishii
Original Article


In previousin vivo studies with mice, rats and monkeys, we have demonstrated that [11C]TMSX ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a potential radioligang for mapping adenosine A2A receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. A suitable preparation method for [11C]TMSX injection was established. The radiation absorbed-dose by [11C]TMSX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of TMSX were not found. The striatal uptake of [11C]TMSX in mice was reduced by pretreatment with theophylline at the dose of 10 and 100mg/kg, suggesting that the [11C]TMSX PET should be carefully performed in the patients received with theophylline. We have concluded that [11C]TMSX is suitable for mapping adenosine A2A receptors in the human brain by PET.

Key words

Adenosine A2A receptor [11C]TMSX central nervous system positron emission tomography 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fredholm BB, Abbracchio MP, Burnstock G, Daly JW, Harden TK, Jacobson KA, et al. Nomenclature and classification of purinoceptors.Pharmacol Rev 1994; 46: 143–156.PubMedGoogle Scholar
  2. 2.
    Haas HL, Selbach O. Functions of neuronal adenosine receptors.Naunyn Schmiedebergs Arch Pharmacol 2000; 362:375–381.PubMedCrossRefGoogle Scholar
  3. 3.
    Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system.Ann Rev Neurosci 2001; 24: 31–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Lewis ME, Patel J, Moon Edley S, Marangos PJ. Autoradiographic visualization of rat brain adenosine receptors usingN 6-cyclohexyl[3H]adenosine.Eur J Pharmacol 1981; 73: 109–110.PubMedCrossRefGoogle Scholar
  5. 5.
    Goodman RR, Snyder SH. Autoradiographic localization of adenosine receptors in rat brain using [3H]cyclohexyladenosine.J Neurosci 1982; 2: 1230–1241.PubMedGoogle Scholar
  6. 6.
    Fastbom J, Pazos A, Palacios JM. The distribution of adenosine A2A receptors and 5′-nucleotidase in the brain of some commonly used experimental animals.Neuroscience 1987; 22: 813–826.PubMedCrossRefGoogle Scholar
  7. 7.
    Fastbom J, Pazos A, Probst A, Palacios JM. Adenosine A2A receptors in the human brain: a quantitative autoradiographic study.Neuroscience 1987; 22: 827–839.PubMedCrossRefGoogle Scholar
  8. 8.
    Svenningsson P, Hall H, Sedvall G, Fredholm BB. Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study.Synapse 1997; 27: 322–335.PubMedCrossRefGoogle Scholar
  9. 9.
    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 1990; 342: 85–89.PubMedCrossRefGoogle Scholar
  10. 10.
    Johansson B, Fredholm B. Further characterization of the binding of the adenosine receptor agonist [3H]CGS 21680 to rat brain using autoradiography.Neuropharmacology 1995; 34: 393–403.PubMedCrossRefGoogle Scholar
  11. 11.
    Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ, et al. D1 and D2 dopamine receptor-regulated gene expression of strionigral and striopallidal neurons.Science 1990; 250: 1429–1432.PubMedCrossRefGoogle Scholar
  12. 12.
    Schiffmann SN, Jacobs O, Vanderhaeghen JJ. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: anin situ hybridization histochemistry study.J Neurochem 1991; 57: 1062–1067.PubMedCrossRefGoogle Scholar
  13. 13.
    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 1993; 631: 161–166.PubMedCrossRefGoogle Scholar
  14. 14.
    Augood SJ, Emson PC. Adenosine A2a receptor mRNA is expressed by enkephalin cells but not by somatostatin cells in rat striatum: a co-expression study.Mol Brain Res 1994; 22: 204–210.PubMedCrossRefGoogle Scholar
  15. 15.
    Kase H. New aspects of physiological and pathophysiological functions of adenosine A2A receptor in basal ganglia.Biosci Biotechnol Biochem 2001; 65: 1447–1457.PubMedCrossRefGoogle Scholar
  16. 16.
    Tissingh G, Booij J, Winogrodzka A, van Royen EA, Wolters EC. IBZM-and CIT-SPECT of the dopaminergic system in parkinsonism.J Neural Transm 1997; 50 (Suppl): 1–7.Google Scholar
  17. 17.
    Stoessl AJ, Ruth TJ. Neuroreceptor imaging: new developments in PET and SPECT imaging of neuroreceptor binding (including dopamine transporters, vesicle transporters and post synaptic receptor sites).Curr Opin Neurol 1998; 11: 327–333.PubMedCrossRefGoogle Scholar
  18. 18.
    Thobois S, Guillouet S, Broussolle E. Contributions of PET and SPECT to the understanding of the pathophysiology of Parkinson’s disease.Neurophysiol Clin 2001; 31: 321–340.PubMedCrossRefGoogle Scholar
  19. 19.
    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 1996; 47: 507–511.PubMedCrossRefGoogle Scholar
  20. 20.
    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 1998; 39: 498–503.PubMedGoogle Scholar
  21. 21.
    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 1998; 45: 312–323.CrossRefGoogle Scholar
  22. 22.
    Ishiwata K, Noguchi J, Wakabayashi S, Shimada J, Ogi N, Nariai T, et al.11C-labeled KF18446: a potential central nervous system adenosine A2a receptor ligand.J Nucl Med 2000; 41: 345–354.PubMedGoogle Scholar
  23. 23.
    Ishiwata K, Ogi N, Shimada J, Nonaka H, Tanaka A, Suzuki F, et al. Further characterization of a CNS adenosine A2a receptor ligand [11C]KF18446 within vitro autoradiography andin vivo tissue uptake.Ann Nucl Med 2000; 14: 81–89.PubMedCrossRefGoogle Scholar
  24. 24.
    Ishiwata K, Shimada J, Wang WF, Harakawa H, Ishii S, Kiyosawa M, et al. Evaluation of iodinated and brominated [11C]styrylxanthine derivatives asin vivo radioligands mapping adenosine A2A receptor in the central nervous system.Ann Nucl Med 2000; 14: 247–253.PubMedCrossRefGoogle Scholar
  25. 25.
    Wang WF, Ishiwata K, Nonaka H, Ishii S, Kiyosawa M, Shimada J, et al. Carbon-11-labeled KF21213: a highly selective ligand for mapping CNS adenosine A2A receptors with positron emission tomography.Nucl Med Biol 2000; 27: 541–546.PubMedCrossRefGoogle Scholar
  26. 26.
    Ishiwata K, Ogi N, Hayakawa N, Oda K, Nagaoka T, Toyama H, et al. Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain following quinolinic acid lesion: comparison with the dopamine receptor imaging.Ann Nucl Med 2002; 16: 467–475.PubMedCrossRefGoogle Scholar
  27. 27.
    Ishiwata K, Shimada J, Ishii K, Suzuki F. Assessment of adenosine A2A receptors with PET as a new diagnostic tool for neurological disorders.Drugs Fut 2002; 27: 569–576.CrossRefGoogle Scholar
  28. 28.
    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 1993; 36: 3731–3733.PubMedCrossRefGoogle Scholar
  29. 29.
    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 1992; 35: 2342–2345.PubMedCrossRefGoogle Scholar
  30. 30.
    Ishiwata K, Seki H, Ishii K, Ishii S, Nozaki T, Senda M. Synthesis andin vivo evaluation of [11C]semotiadil, a benzothiazine calcium antagonist.Appl Radiat Isot 1994; 45: 439–443.PubMedCrossRefGoogle Scholar
  31. 31.
    Ishiwata K, Ido T, Mejia AA, Ichihashi M, Mishima Y. Synthesis and radiation dosimetry of 4-borono-2-[18F]fluoro-D,L-phenylalanine: A target compound for PET and boron neutron capture therapy.Appl Radiat Isot 1991; 142: 325–328.Google Scholar
  32. 32.
    Mejia AA, Nakamura T, Itoh M, Hatazawa J, Ishiwata K, Ido T, et al. Absorbed dose estimates in positron emission tomography studies based on the administration of18F-labeled radiopharmaceuticals.J Radiat Res 1991; 32: 243–261.PubMedCrossRefGoogle Scholar
  33. 33.
    Ishiwata K, Sakiyama Y, Sakiyama T, Shimada J, Toyama H, Oda K, et al. Myocardial adenosine A2a receptor imaging of rabbit by PET with [11C]KF17837.Ann Nucl Med 1997; 11: 219–225.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2003

Authors and Affiliations

  • Kiichi Ishiwata
    • 1
  • Wei-Fang Wang
    • 1
  • Yuichi Kimura
    • 1
  • Kazunori Kawamura
    • 1
  • Kenji Ishii
    • 1
  1. 1.Positron Medical CenterTokyo Metropolitan Institute of GerontologyTokyoJapan

Personalised recommendations