Synthesis and characterization of [76Br]-labeled high-affinity A3 adenosine receptor ligands for positron emission tomography

IntroductionBromine-76-radiolabeled analogues of previously reported high-affinity A3 adenosine receptor (A3AR) nucleoside ligands have been prepared as potential radiotracers for positron emission tomography.MethodsThe radiosyntheses were accomplished by oxidative radiobromination on the N6-benzyl moiety of trimethyltin precursors. Biodistribution studies of the kinetics of uptake were conducted in awake rats.ResultsWe prepared an agonist ligand {[76Br](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/μmol and an antagonist ligand {[76Br](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/μmol. The resultant products exhibited the expected high affinity (Ki∼0.6 nM) and specific binding at the human A3AR 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 A3AR, over a 2-h time course, which suggests the presence of a specific A3AR retention mechanism.ConclusionWe were able to compare uptake of the [76Br]-labeled antagonist MRS5147 to [76Br]agonist MRS3581. The antagonist MRS5147 shows increasing uptake in the testes, an A3AR-rich tissue, suggesting that this ligand may have promise as a molecular imaging agent.