title: Synthesis and characterization of [76Br]-labeled high-affinity A3 adenosine receptor ligands for positron emission tomography.
abstract: BACKGROUND
  Bromine-76-radiolabeled analogues of previously reported high-affinity A(3) adenosine receptor (A(3)AR) nucleoside ligands have been prepared as potential radiotracers for positron emission tomography.
  
  
  METHODS
  The radiosyntheses were accomplished by oxidative radiobromination on the N(6)-benzyl moiety of trimethyltin precursors. Biodistribution studies of the kinetics of uptake were conducted in awake rats.
  
  
  RESULTS
  We prepared an agonist ligand {[(76)Br](1'S,2'R,3'S,4'R,5'S)-4'-{2-chloro-6-[(3-bromophenylmethyl)amino]purin-9-yl}-1'-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2',3'-diol (MRS3581)} in 59% radiochemical yield with a specific activity of 19.5 GBq/micromol and an antagonist ligand {[(76)Br](1'R,2'R,3'S,4'R,5'S)-4'-(6-(3-bromobenzylamino)-2-chloro-9H-purin-9-yl)bicyclo[3.1.0]hexane-2',3'-diol (MRS5147)} in 65% radiochemical yield with a specific activity of 22 GBq/micromol. The resultant products exhibited the expected high affinity (K(i) approximately 0.6 nM) and specific binding at the human A(3)AR in vitro. Biodistribution studies in the rat showed uptake in the organs of excretion and metabolism. The antagonist MRS5147 exhibited increasing uptake in testes, an organ that contains significant quantities of A(3)AR, over a 2-h time course, which suggests the presence of a specific A(3)AR retention mechanism.
  
  
  CONCLUSIONS
  We were able to compare uptake of the [(76)Br]-labeled antagonist MRS5147 to [(76)Br]agonist MRS3581. The antagonist MRS5147 shows increasing uptake in the testes, an A(3)AR-rich tissue, suggesting that this ligand may have promise as a molecular imaging agent.
authors.affiliation: Positron Emission Tomography Radiochemistry Group, NIBIB, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. dk7k@nih.gov
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Lixin
authors.initials: L
authors.lastname: Lang
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Abesh Kumar
authors.initials: AK
authors.lastname: Bhattacharjee
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Bhalchandra V
authors.initials: BV
authors.lastname: Joshi
authors.forename: Artem
authors.initials: A
authors.lastname: Melman
authors.forename: Sonia
authors.initials: S
authors.lastname: de Castro
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001967:Bromine Radioisotopes / Q000737:chemistry*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D009705:Nucleosides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D013194:Staining and Labeling; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D001967:Bromine Radioisotopes; D008024:Ligands; D009705:Nucleosides; D043684:Receptor, Adenosine A3