In vivo labelling of the adenosine A2A receptor in mouse brain using the selective antagonist [3H]SCH 58261.
The selective A2A receptor antagonist [3H]SCH 58261 was injected intravenously in mice and the radioactivity accumulating in various brain regions was determined by tissue sampling. Radioactivity levels in regions of interest such as the striatum were highest 15 min after injection and quickly declined thereafter (30 min and 1 h postinjection) in a time-dependent manner. The amount of labelling was ranked as follows: striatum (4.6 +/- 0.3 fmol/mg protein) >> cortex > hippocampus > pons = hypothalamus > cerebellum (0.5 +/- 0.05 fmol/mg protein). Specific labelling of the A2A receptor occurred in striatum and cortex because significantly less radioactivity accumulated in these areas from adenosine A2A receptor knockout mice as compared to wild-type littermates. In control outbred CD1 mice, a striatum-to-cerebellum ratio of 7.6 +/- 0.6 was found. At 30 min postinjection, the nonselective adenosine receptor antagonist caffeine reduced the radioactivity due to [3H]SCH 58261 in the striatum by 32% at 1 mg/kg i.p. and by 66% at the stimulant dose of 6.25 mg/kg i.p. Radioactivity in the striatum was lowered, respectively, by 66 and 86% 30 min after injection of 3 or 10 mg/kg i.p. doses of unlabelled SCH 58261. The present results indicate that [3H]SCH 58261 directly labels striatal A2A receptors in vivo. Thus [3H]SCH 58261 is an excellent tool for studying brain distribution and A2A receptor occupancy of various compounds ranging from xanthines, such as caffeine, to other A2A antagonists.
El Yacoubi
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M
UMR CNRS 6036, IFRMP 23, U.F.R. de Médecine & Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.
Ledent
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C
Parmentier
M
M
Ongini
E
E
Costentin
J
J
Vaugeois
J M
JM
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000378:metabolism*; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000172:deficiency / Q000235:genetics; D014230:Triazoles / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014230:Triazoles; D014316:Tritium; D002110:Caffeine; D000241:Adenosine