Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, Germany.
Pharma Center Bonn, Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
Int J Mol Sci. 2020 Apr 30;21(9):3197. doi: 10.3390/ijms21093197.
The adenosine A 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 receptor ligand was synthesized, containing a 2-fluoropyridine moiety suitable for labeling with the short-lived PET radionuclide fluorine-18. Compound showed a high binding affinity for the human A receptor (K(A) = 2.51 nM), along with high selectivities versus the A, A, and A receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [F]F/K/KCO in DMSO at 120 °C. Metabolic studies of 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 , corresponding to the known ubiquitous but low expression of the A receptor. Consequently, represents a novel PET radiotracer with high affinity and selectivity toward the adenosine A receptor and a suitable in vivo profile. Subsequent studies are envisaged to investigate the applicability of to detect alterations in the receptor density in certain cancer-related disease models.
腺嘌呤 A 受体已被提议作为癌症的一种新的治疗靶点，因为它在几种肿瘤和癌细胞中的表达明显升高。通过正电子发射断层扫描 (PET) 进行非侵入性分子成像将允许在体内定量检测该受体在病理过程中的表达，并很可能能够识别和临床监测相应的癌症治疗方法。基于双环吡啶并嘧啶-2,4-二酮核心结构，合成了新型腺嘌呤 A 受体配体，其中含有适合用短寿命的 PET 放射性核素氟-18 标记的 2-氟吡啶部分。化合物对人 A 受体具有高亲和力（K(A) = 2.51 nM），对 A、A 和 A 受体亚型具有高选择性。因此，它通过用 [F]F/K/KCO 在 DMSO 中于 120°C 进行相应的硝基前体的亲核芳香取代反应进行放射性标记。在小鼠中的代谢研究表明，在 30 分钟时，血浆中约有 60%的放射性示踪剂保持完整。在健康小鼠中的初步 PET 研究表明，总的示踪剂分布与已知的普遍存在但低表达的 A 受体一致。因此， 代表了一种新型的具有高亲和力和选择性的腺嘌呤 A 受体 PET 放射性示踪剂，具有合适的体内特征。随后的研究旨在研究 用于检测某些与癌症相关的疾病模型中受体密度变化的适用性。
