Abstract：
Imaging of the A1 adenosine receptor (A1R) by positron emission tomography (PET) with 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propyl-xanthine ([18F]CPFPX) has been widely used in preclinical and clinical studies. However, this radioligand suffers from rapid peripheral metabolism and subsequent accumulation of radiometabolites in the vascular compartment. In the present work, we prepared four derivatives of CPFPX by replacement of the cyclopentyl group with norbornane moieties. These derivatives were evaluated by competition binding studies, microsomal stability assays and LC-MS analysis of microsomal metabolites. In addition, the 18F-labeled isotopologue of 8-(1-norbornyl)-3-(3-fluoropropyl)-1-propylxanthine (1-NBX) as the most promising candidate was prepared by radiofluorination of the corresponding tosylate precursor and the resulting radioligand ([18F]1-NBX) was evaluated by permeability assays with Caco-2 cells and in vitro autoradiography in rat brain slices. Our results demonstrate that 1-NBX exhibits significantly improved A1R affinity and selectivity when compared to CPFPX and that it does not give rise to lipophilic metabolites expected to cross the blood-brain-barrier in microsomal assays. Furthermore, [18F]1-NBX showed a high passive permeability (Pc = 6.9 ± 2.9 × 10-5 cm/s) and in vitro autoradiography with this radioligand resulted in a distribution pattern matching A1R expression in the brain. Moreover, a low degree of non-specific binding (5%) was observed. Taken together, these findings identify [18F]1-NBX as a promising candidate for further preclinical evaluation as potential PET tracer for A1R imaging.
摘要：
通过8-环戊基-3-（3-[18F]氟丙基）-1-丙基-黄嘌呤（[18F]CPFPX）的正电子发射断层扫描（PET）对A1腺苷受体（A1R）进行成像已广泛用于临床前和临床研究。然而,这种放射性配体具有快速的外周代谢和随后在血管室中放射性代谢物的积累。在目前的工作中,我们通过用降冰片烷部分取代环戊基制备了CPFPX的四种衍生物。这些衍生物通过竞争结合研究进行评估，微粒体稳定性测定和微粒体代谢物的LC-MS分析。此外,8-（1-降冰片基）-3-（3-氟丙基）-1-丙基黄嘌呤（1-NBX）作为最有希望的候选物的18F标记同位素是通过相应的甲苯磺酸盐前体的放射性氟化制备的，并通过Caco-2细胞的通透性测定和大鼠脑切片的体外放射造影来评估所得放射性配体（[18F]1-NBX）。我们的结果表明，与CPFPX相比，1-NBX表现出显着提高的A1R亲和力和选择性，并且在微粒体测定中不会产生预期会穿过血脑屏障的亲脂性代谢物。此外，[18F]1-NBX显示出高被动通透性（Pc=6.9±2.9×10-5cm/s），并且使用该放射性配体进行体外放射自显影术导致与脑中A1R表达匹配的分布模式。此外，观察到低程度的非特异性结合(5%)。一起来看,这些发现将[18F]1-NBX作为A1R成像的潜在PET示踪剂作为进一步临床前评估的有希望的候选者.
