Abstract
The G protein-coupled adenosine A2B 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 A2B 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 A2B 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 (SUV3min: 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 A2B receptor (Ki (5) = 9.97 ± 0.86 nM; Ki (6) = 12.3 ± 3.6 nM) with moderate selectivity versus the other adenosine receptor subtypes.
Highlights
Published: 19 May 2021Adenosine is an important signaling molecule that is released from cells or generated extracellularly after the cleavage of adenosine 5’-triphosphate (ATP) by ectonucleotidases.Extracellular adenosine activates G protein-coupled receptors, which are classified into four subtypes: adenosine A1, A2A, A2B, and A3 receptors [1,2,3,4]
A biodistribution study with [3 H]PSB-603 resulted in a low brain uptake with an standardized uptake value (SUV) of 0.2
Fluorine was introduced into the molecule to allow the possibility for future radiolabeling with fluorine-18. Both novel fluorinated compounds 5 and 6 showed high binding affinity towards the A2B receptor (Ki values of about 10 nM) and moderate selectivity towards the other adenosine receptor subtypes (A1, A2A, and A3 ). These findings provide a good basis for further modifications of the ligand structure to enhance selectivity towards the adenosine receptor subtypes with respect to future brain positron emission tomography (PET) imaging of the adenosine A2B receptor
Summary
Published: 19 May 2021Adenosine is an important signaling molecule that is released from cells or generated extracellularly after the cleavage of adenosine 5’-triphosphate (ATP) by ectonucleotidases.Extracellular adenosine activates G protein-coupled receptors, which are classified into four subtypes: adenosine A1 , A2A , A2B , and A3 receptors [1,2,3,4]. Compared to the other subtypes, the adenosine A2B receptor (A2B receptor) has a low expression under physiological conditions and is only activated at higher adenosine concentrations [1,5]. Such high levels can be reached under pathophysiological conditions (e.g., inflammation, cancer, infection, and hypoxia) [6]. Due to its involvement in tumor growth, angiogenesis, metastasis, and immunomodulation, the A2B receptor is an interesting target for the imaging and treatment of cancer [7,8] It shows an increased expression in various solid tumors and tumor cell lines relative to normal tissues. These findings can be an outcome of the hypoxic conditions and is associated with increased adenosine concentrations in the tumor microenvironment [9,10,11]
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