Annals of Nuclear Medicine

, Volume 16, Issue 6, pp 377–382 | Cite as

Preclinical studies on [11C]MPDX for mapping adenosine A1 receptors by positron emission tomography

  • Kiichi IshiwataEmail author
  • Tadashi Nariai
  • Yuichi Kimura
  • Keiichi Oda
  • Kazunori Kawamura
  • Kenji Ishii
  • Michio Senda
  • Shinichi Wakabayashi
  • Junichi Shimada
Original Articles


In previousin vivo studies with mice, rats and cats, we have demonstrated that [11C]MPDX ([1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A1 receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [11C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [11C]MPDX. We have concluded that [11C]MPDX is suitable for mapping adenosine A1 receptors in the human brain by PET.

Key words

adenosine A1 receptor [11C]MPDX central nervous system positron emission tomography 


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  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.
    Palmer TM, Stiles GL. Adenosine receptors.Neuropharmacology 1995; 34: 683–694.PubMedCrossRefGoogle Scholar
  3. 3.
    Ongini E, Fredholm BB. Pharmacology of adenosine A2A receptors.Trends Pharmacol Sci 1996; 17: 364–372.PubMedCrossRefGoogle Scholar
  4. 4.
    Haas HL, Selbach O. Functions of neuronal adenosine receptors.Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 375–381.PubMedCrossRefGoogle Scholar
  5. 5.
    Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system.Ann Rev Neurosci 2001; 24: 31–55.PubMedCrossRefGoogle Scholar
  6. 6.
    von Lubitz DK. Adenosine in the treatment of stroke: yes, maybe, or absolutely not?Expert Opin Investig Drugs 2001; 10: 619–632.CrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Goodman RR, Snyder SH. Autoradiographic localization of adenosine receptors in rat brain using [3H]cyclohexyladenosine.J Neurosci 1982; 2: 1230–1241.PubMedGoogle Scholar
  9. 9.
    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 1987; 22: 813–826.PubMedCrossRefGoogle Scholar
  10. 10.
    Fastbom J, Pazos A, Probst A, Palacios JM. Adenosine A1 receptors in the human brain: a quantitative autoradiographic study.Neuroscience 1987; 22: 827–839.PubMedCrossRefGoogle Scholar
  11. 11.
    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
  12. 12.
    Schindler M, Harris CA, Hayes B, Papotti M, Humphrey PP. Immunohistochemical localization of adenosine A1 receptors in human brain regions.Neurosci Lett 2001; 297: 211–215.PubMedCrossRefGoogle Scholar
  13. 13.
    Mally J, Stone TW. Potential role of adenosine antagonist therapy in pathological tremor disorders.Pharmacol Ther 1996; 72: 243–250.PubMedCrossRefGoogle Scholar
  14. 14.
    Ishiwata K, Furuta R, Shimada J, Ishii S, Endo K, Suzuki F, et al. Synthesis and preliminary evaluation of [11C]KF15372, a selective adenosine A1 antagonist.Appl Radiat Isot 1995; 46: 1009–1013.PubMedCrossRefGoogle Scholar
  15. 15.
    Furuta R, Ishiwata K, Kiyosawa M, Ishii S, Saito N, Shimada J, et al. Carbon-11 labeled KF15372: a potential central nervous system adenosine A1 receptor ligand.J Nucl Med 1996; 37: 1203–1207.PubMedGoogle Scholar
  16. 16.
    Noguchi J, Ishiwata K, Furuta R, Shimada J, Kiyosawa M, Ishii S, et al. Evaluation of carbon-11 labeled KF15372 and it's ethyl and methyl derivatives as a potential CNS adenosine A1 receptor ligand.Nucl Med Biol 1997; 24: 53–59.PubMedCrossRefGoogle Scholar
  17. 17.
    Wakabayashi S, Nariai T, Ishiwata K, Nagaoka T, Hirakawa K, Oda K, et al. A PET study of adenosine A1 receptor in anesthetized monkey brain.Nucl Med Biol 2000; 27: 401–406.PubMedCrossRefGoogle Scholar
  18. 18.
    Shimada Y, Ishiwata K, Kiyosawa M, Nariai T, Oda K, Toyama H, et al. Mapping adenosine A1 receptors in the cat brain by positron emission tomography with [11C]MPDX.Nucl Med Biol 2002; 29: 29–37.PubMedCrossRefGoogle Scholar
  19. 19.
    Kiyosawa M, Ishiwata K, Noguchi J, Endo K, Wang WF, Suzuki F, et al. Neuroreceptor bindings and synaptic activity in visual system of monocularly enucleated rat.Jpn J Ophthalmol 2001; 45: 264–269.PubMedCrossRefGoogle Scholar
  20. 20.
    Shimada Y, Nariai T, Ishiwata K, Ishii S, Oda K, Ando M, et al. Decrease in adenosine A1 receptor binding potential after reperfusion as a predictor of severe cerebral ischemic insult—PET multitracer study in cats' model of transient MCA occlusion.J Cereb Blood Flow Metab 1999; 19: S249.Google Scholar
  21. 21.
    Shimada J, Suzuki F, Nonaka H, Karasawa A, Mizumoto H, Ohno T, et al. 8-(Dicyclopropylmethyl)-1,3-dispropylxanthine: a potent and selective adenosine A1 antagonist with renal protective and diuretic activities.J Med Chem 1991; 34: 466–469.PubMedCrossRefGoogle Scholar
  22. 22.
    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 1992; 35: 3066–3075.PubMedCrossRefGoogle Scholar
  23. 23.
    Suzuki F, Shimada J, Shiozaki S, Ichikawa S, Ishii A, Nakamura J, et al. Adenosine A1 antagonists. 3. Structure-activity relationships on amelioration against scopolamine-orN 6-(R-phenylisopropyl)adenosine-induced cognitive disturbance.J Med Chem 1993; 36: 2508–2518.PubMedCrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    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
  26. 26.
    Watanabe M, Uchida H, Okada H, Shimizu K, Satoh N, Yoshikawa E, et al. A high resolution PET for animal studies.IEEE Trans Med Imag 1992; 11: 577–580.CrossRefGoogle Scholar
  27. 27.
    Jansen K, Faull RLM, Dragunow M, Synek BJL. Alzheimer's disease: changes in hippocampalN-methyl-d-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—an autoradiographic study.Neuroscience 1990; 39: 613–627.PubMedCrossRefGoogle Scholar
  28. 28.
    Ulas J, Brunner LC, Nguyen L, Cotman CW. Reduced density of adenosine A1 receptors and preserved coupling of adenosine A1 receptors to G proteins in Alzheimer hippocampus: a quantitative autoradiographic study.Neuroscience 1993; 52: 843–854.PubMedCrossRefGoogle Scholar
  29. 29.
    Angelatou F, Pagonopoulou O, Maraziotis T, Olivier A, Villemeure JG, Avoli M, et al. Upregulation of A1 adenosine receptors in human temporal lobe epilepsy: a quantitative autoradiographic study.Neurosci Lett 1993; 163: 11–14.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2002

Authors and Affiliations

  • Kiichi Ishiwata
    • 1
    Email author
  • Tadashi Nariai
    • 2
  • Yuichi Kimura
    • 1
  • Keiichi Oda
    • 1
  • Kazunori Kawamura
    • 1
  • Kenji Ishii
    • 1
  • Michio Senda
    • 1
  • Shinichi Wakabayashi
    • 2
  • Junichi Shimada
    • 3
  1. 1.Positron Medical CenterTokyo Metropolitan Institute of GerontologyTokyoJapan
  2. 2.Department of NeurosurgeryTokyo Medical and Dental UniversityTokyoJapan
  3. 3.Pharmaceutical Research InstituteKyowa Hakko Kogyo Co., Ltd.KyowaJapan

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