title: Small-animal PET study of adenosine A(1) receptors in rat brain: blocking receptors and raising extracellular adenosine.
abstract: Activation of adenosine A(1) receptors (A(1)R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A(1)R can be visualized using 8-dicyclopropylmethyl-1-(11)C-methyl-3-propyl-xanthine ((11)C-MPDX) and PET. This study aims to test whether (11)C-MPDX can be used for quantitative studies of cerebral A(1)R in rodents.
  
  
  METHODS
  (11)C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A(1)R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A(1)R, whereas ethanol and ABT-702 increase extracellular adenosine.
  
  
  RESULTS
  In groups 1 and 3, the brain was clearly visualized. High uptake of (11)C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%-45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2-tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K(1)/k(2) from the model fit) was not altered under the study conditions.
  
  
  CONCLUSIONS
  (11)C-MPDX shows a regional distribution in rat brain consistent with binding to A(1)R. Tracer binding is blocked by the selective A(1)R antagonist DPCPX. Pretreatment of animals with ethanol and adenosine kinase inhibitor increases (11)C-MPDX uptake. This increase may reflect an increased availability of A(1)R after acute exposure to ethanol.
authors.affiliation: Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Soumen
authors.initials: S
authors.lastname: Paul
authors.forename: Shivashankar
authors.initials: S
authors.lastname: Khanapur
authors.forename: Anna A
authors.initials: AA
authors.lastname: Rybczynska
authors.forename: Chantal
authors.initials: C
authors.lastname: Kwizera
authors.forename: Jurgen W A
authors.initials: JW
authors.lastname: Sijbesma
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Antoon T M
authors.initials: AT
authors.lastname: Willemsen
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000248:Adenosine Kinase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002247:Carbon Isotopes / Q000494:pharmacology; D000431:Ethanol / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis*; D014018:Tissue Distribution; D014970:Xanthines / Q000494:pharmacology
chemical_list: C451639:1-methyl-8-dicyclopropylmethyl-1-methyl-3-propylxanthine; D002247:Carbon Isotopes; D008024:Ligands; D043682:Receptor, Adenosine A1; D014970:Xanthines; D000431:Ethanol; D000248:Adenosine Kinase; D000241:Adenosine