Development of a Radiofluorinated Adenosine A 2B Receptor Antagonist as Potential Ligand for PET Imaging.

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 A ₁ , A _2A , and A ₃ receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [ ¹⁸ F]F ^- /K _2.2.2. /K ₂ CO ₃ in DMSO at 120 °C. Metabolic studies of [ ¹⁸ F]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 [ ¹⁸ F]9 , corresponding to the known ubiquitous but low expression of the A _2B receptor. Consequently, [ ¹⁸ F]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 [ ¹⁸ F]9 to detect alterations in the receptor density in certain cancer-related disease models.
Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.