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The G protein-coupled adenosine A_2B receptor is suggested to be involved in various pathological processes accompanied by increased levels of adenosine as found in inflammation, hypoxia, and cancer. Therefore, the adenosine A_2B receptor is currently in focus as a novel target for cancer therapy as well as for noninvasive molecular imaging via positron emission tomography (PET). Aiming at the development of a radiotracer labeled with the PET radionuclide fluorine-18 for imaging the adenosine A_2B receptor in brain tumors, one of the most potent and selective antagonists, the xanthine derivative PSB-603, was selected as a lead compound. As initial biodistribution studies in mice revealed a negligible brain uptake of [³H]PSB-603 (SUV_3min: 0.2), structural modifications were performed to optimize the physicochemical properties regarding blood–brain barrier penetration. Two novel fluorinated derivatives bearing a 2-fluoropyridine (<b>5</b>) moiety and a 4-fluoro-piperidine (<b>6</b>) moiety were synthesized, and their affinity towards the four adenosine receptor subtypes was determined in competition binding assays. Both compounds showed high affinity towards the adenosine A_2B receptor (<i>K</i>_i (<b>5</b>) = 9.97 ± 0.86 nM; <i>K</i>_i (<b>6</b>) = 12.3 ± 3.6 nM) with moderate selectivity versus the other adenosine receptor subtypes.