Abstract
The adenosine A2B 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 A2B 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 A2B receptor (Ki(A2B) = 2.51 nM), along with high selectivities versus the A1, A2A, and A3 receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [18F]F-/K2.2.2./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 A2B receptor. Consequently, [18F]9 represents a novel PET radiotracer with high affinity and selectivity toward the adenosine A2B 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.
Highlights
Adenosine receptors belong to the family of G-protein-coupled receptors and are activated by the purine nucleoside adenosine, a precursor and degradation product of adenine nucleotides such as adenosine 5 -triphosphate (ATP)
The relevance of A2B receptor in promoting cancer progression has been revealed via mechanisms such as tumor growth, angiogenesis, metastasis, and immunomodulation, and it has been shown that its expression can be drastically increased in tumors and cancer cells, as recently reviewed [6,9,10,11]
Current pharmaceutical studies indicate that the A2B receptor might be appropriate for cancer therapies in comparison to other adenosine receptor subtypes that show to some extend both pro- and antitumor effects [7,9,12]
Summary
Adenosine receptors belong to the family of G-protein-coupled receptors and are activated by the purine nucleoside adenosine, a precursor and degradation product of adenine nucleotides such as adenosine 5 -triphosphate (ATP). The effects of adenosine are mediated via the four receptor subtypes A1, A2A, A2B, and A3. Each of these exhibits distinct pharmacological properties, cell and tissue distribution, and intracellular signaling [1,2,3]. In recent years, the involvement of the A2B receptor in pathophysiological processes was discovered to be driven by the fact that extracellular concentrations of adenosine increase under certain pathological conditions such as hypoxia or inflammation [6,7,8]. Current pharmaceutical studies indicate that the A2B receptor might be appropriate for cancer therapies in comparison to other adenosine receptor subtypes that show to some extend both pro- and antitumor effects [7,9,12]
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