Petroni Debora, Giacomelli Chiara, Taliani Sabrina, Barresi Elisabetta, Robello Marco, Daniele Simona, Bartoli Antonietta, Burchielli Silvia, Pardini Silvia, Salvadori Piero A, Da Settimo Federico, Martini Claudia, Trincavelli Maria Letizia, Menichetti Luca
Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124 Pisa, Italy.
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
Nucl Med Biol. 2016 May;43(5):309-17. doi: 10.1016/j.nucmedbio.2016.02.005. Epub 2016 Feb 27.
A2B adenosine receptors (ARs) are commonly defined as "danger" sensors because they are triggered during cell injury when the endogenous molecule, adenosine, increases rapidly. These receptors, together with the other receptor subtypes (A1, A2A and A3), exert a wide variety of immunomodulating and (cyto)protective effects, thus representing a pivotal therapeutic target for different pathologies including diabetes, tumors, cardiovascular diseases, pulmonary fibrosis and others. The limited availability of potent and selective ligands for A2B ARs has prevented this receptor to emerge both as therapeutic and diagnostic target.
Recently, a new class of potent A2B ARs antagonists was developed featuring the triazinobenzimidazole scaffold. Starting from this chemotype, we synthesized a new radiotracer, [(11)C]-4 (1-[(11)C]methyl-3-phenyl triazino[4,3-a]benzimidazol-4(1H)-one), and investigated the pharmacokinetics of this compound in vivo to define its potential use in the imaging of A2B AR with positron emission tomography.
[(11)C]-4 showed a very high chemical and blood stability. Results of in vivo and ex vivo experiments underlined the ability of this molecule to bind the A2B AR and correlated with the A2B AR protein and gene expression data.
Although further studies are necessary, these data suggest that [(11)C]-4 may represent a good lead compound for the development of novel selective and potent A2B AR radiotracers, and a new option for the clinical investigation of several pathophysiological processes and chronic diseases.
A2B腺苷受体（ARs）通常被定义为“危险”传感器，因为在细胞损伤期间，当内源性分子腺苷迅速增加时，它们会被激活。这些受体与其他受体亚型（A1、A2A和A3）一起，发挥多种免疫调节和（细胞）保护作用，因此代表了包括糖尿病、肿瘤、心血管疾病、肺纤维化等不同病理的关键治疗靶点。A2B ARs有效和选择性配体的可用性有限，阻碍了该受体成为治疗和诊断靶点。
最近，开发了一类以三嗪并苯并咪唑支架为特征的新型A2B ARs拮抗剂。从这种化学类型出发，我们合成了一种新的放射性示踪剂[(11)C]-4（1-[(11)C]甲基-3-苯基三嗪并[4,3-a]苯并咪唑-4(1H)-酮），并研究了该化合物在体内的药代动力学，以确定其在正电子发射断层扫描成像A2B AR中的潜在用途。
[(11)C]-4显示出非常高的化学和血液稳定性。体内和体外实验结果强调了该分子结合A2B AR的能力，并与A2B AR蛋白和基因表达数据相关。
尽管还需要进一步研究，但这些数据表明[(11)C]-4可能是开发新型选择性和有效A2B AR放射性示踪剂的良好先导化合物，也是临床研究几种病理生理过程和慢性疾病的新选择。
