Synthesis of Novel Fluorinated Xanthine Derivatives with High Adenosine A(2B) Receptor Binding Affinity

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 [(3)H]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 (5) moiety and a 4-fluoro-piperidine (6) 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 (K(i) (5) = 9.97 ± 0.86 nM; K(i) (6) = 12.3 ± 3.6 nM) with moderate selectivity versus the other adenosine receptor subtypes.