The adenosine A_2B receptor has been proposed as a novel therapeutic target in cancer, as its expression is drastically elevated in several tumors and cancer cells. Noninvasive molecular imaging via positron emission tomography (PET) would allow the in vivo quantification of this receptor in pathological processes and most likely enable the identification and clinical monitoring of respective cancer therapies. On the basis of a bicyclic pyridopyrimidine-2,4-dione core structure, the new adenosine A_2B receptor ligand 9 was synthesized, containing a 2-fluoropyridine moiety suitable for labeling with the short-lived PET radionuclide fluorine-18. Compound 9 showed a high binding affinity for the human A_2B receptor (K_i(A_2B) = 2.51 nM), along with high selectivities versus the A₁, A_2A, and A₃ receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [¹⁸F]F^-/K_2.2.2./K₂CO₃ in DMSO at 120 °C. Metabolic studies of [¹⁸F]9 in mice revealed about 60% of radiotracer intact in plasma at 30 minutes p.i. A preliminary PET study in healthy mice showed an overall biodistribution of [¹⁸F]9, corresponding to the known ubiquitous but low expression of the A_2B receptor. Consequently, [¹⁸F]9 represents a novel PET radiotracer with high affinity and selectivity toward the adenosine A_2B receptor and a suitable in vivo profile. Subsequent studies are envisaged to investigate the applicability of [¹⁸F]9 to detect alterations in the receptor density in certain cancer-related disease models.

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 (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.