Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
UMR 1240 INSERM IMOST, Université Clermont-Auvergne, Clermont-Ferrand, France.
Bioorg Chem. 2019 May;86:346-362. doi: 10.1016/j.bioorg.2019.01.037. Epub 2019 Jan 28.
With the aim to develop a specific radioligand for imaging the cyclic nucleotide phosphodiesterase 5 (PDE5) in brain by positron emission tomography (PET), seven new fluorinated inhibitors (3-9) were synthesized on the basis of a quinoline core. The inhibitory activity for PDE5 together with a panel of other PDEs was determined in vitro and two derivatives were selected for IC value determination. The most promising compound 7 (IC = 5.92 nM for PDE5A), containing a 3-fluoroazetidine moiety, was further radiolabeled by aliphatic nucleophilic substitution of two different leaving groups (nosylate and tosylate) using [F]fluoride. The use of the nosylate precursor and tetra-n-butyl ammonium [F]fluoride ([F]TBAF) in 3-methyl-3-pentanol combined with the addition of a small amount of water proved to be the best radiolabeling conditions achieving a RCY of 4.9 ± 1.5% in an automated procedure. Preliminary biological investigations in vitro and in vivo were performed to characterize this new PDE5 radioligand. Metabolism studies of [F]7 in mice revealed a fast metabolic degradation with the formation of radiometabolites which have been detected in the brain.
为了开发一种用于正电子发射断层扫描（PET）成像脑中环核苷酸磷酸二酯酶 5（PDE5）的特异性放射性配体，我们基于喹啉核心合成了七种新的氟化抑制剂（3-9）。在体外测定了它们对 PDE5 及一系列其他 PDE 的抑制活性，并选择了两种衍生物进行 IC 值测定。最有前途的化合物 7（对 PDE5A 的 IC = 5.92 nM），含有 3-氟氮杂环丁烷部分，通过使用[F]氟化物对两种不同离去基团（对甲苯磺酰基和甲苯磺酰基）进行脂肪亲核取代进一步进行放射性标记。使用对甲苯磺酰基前体和四丁基铵[F]氟化物（[F]TBAF）在 3-甲基-3-戊醇中，并加入少量水，被证明是最佳的放射性标记条件，在自动化程序中实现了 4.9 ± 1.5%的 RCY。进行了体外和体内初步生物学研究以表征这种新的 PDE5 放射性配体。在小鼠中进行的[F]7 的代谢研究表明，其代谢降解速度很快，形成了在大脑中检测到的放射性代谢产物。
