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首页> 外文期刊>RSC Advances >Deuteration versus ethylation – strategies to improve the metabolic fate of an 18F-labeled celecoxib derivative
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Deuteration versus ethylation – strategies to improve the metabolic fate of an 18F-labeled celecoxib derivative

机译：氘与乙基化 - 改善18F标记的Celecoxib衍生物的代谢命运的策略

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The inducible isoenzyme cyclooxygenase-2 (COX-2) is closely associated with chemo-/radioresistance and poor prognosis of solid tumors. Therefore, COX-2 represents an attractive target for functional characterization of tumors by positron emission tomography (PET). In this study, the celecoxib derivative 3-([ ~(18) F]fluoromethyl)-1-[4-(methylsulfonyl)phenyl]-5-( p -tolyl)-1 H -pyrazole ([ ~(18) F] 5a ) was chosen as a lead compound having a reported high COX-2 inhibitory potency and a potentially low carbonic anhydrase binding tendency. The respective deuterated analog [D _(2) , ~(18) F] 5a and the fluoroethyl-substituted derivative [ ~(18) F] 5b were selected to study the influence of these modifications with respect to COX inhibition potency in vitro and metabolic stability of the radiolabeled tracers in vivo . COX-2 inhibitory potency was found to be influenced by elongation of the side chain but, as expected, not by deuteration. An automated radiosynthesis comprising ~(18) F-fluorination and purification under comparable conditions provided the radiotracers [ ~(18) F] 5a,b and [D _(2) , ~(18) F] 5a in good radiochemical yields (RCY) and high radiochemical purity (RCP). Biodistribution and PET studies comparing all three compounds revealed bone accumulation of ~(18) F-activity to be lowest for the ethyl derivative [ ~(18) F] 5b . However, the deuterated analog [D _(2) , ~(18) F] 5a turned out to be the most stable compound of the three derivatives studied here. Time-dependent degradation of [ ~(18) F] 5a,b and [D _(2) , ~(18) F] 5a after incubation in murine liver microsomes was in accordance with the data on metabolism in vivo . Furthermore, metabolites were identified based on UPLC-MS/MS.
机译：诱导型同工酶环氧化酶-2（COX-2）与化学/辐射敏感度和固体瘤的预后不良密切相关。因此，COX-2表示通过正电子发射断层扫描（PET）的肿瘤功能表征的有吸引力的靶标。在该研究中，Celecoxib衍生物3 - （[〜（18）f]氟甲基）-1- [4-（甲基磺酰基）苯基] -5-（p-丙基）-1h-吡唑（[〜（18）f选择5a）作为具有报告的高COX-2抑制效力的铅化合物和潜在低碳酸酐基结合趋势。选择各自的氘代模数[D _（2），〜（18）F] 5A和氟乙基取代的衍生物[〜（18）F] 5B，以研究这些修饰对体外COX抑制效力的影响体内放射性标记跟踪器的代谢稳定性。发现COX-2抑制效力受侧链伸长的影响，但是如预期的那样，不是由氘化。包含〜（18）F-氟化和在可比条件下的纯化的自动辐射合成，提供了放射性机构[〜（18）f] 5a，b和[d _（2），〜（18）f] 5a，良好的放射化学产量（Rcy ）和高放射化学纯度（RCP）。与所有三种化合物的生物分布和宠物研究表明，对于乙基衍生物[〜（18）F] 5b，〜（18）F活性的骨积累最低。然而，氘代的模拟[d _（2），〜（18）f] 5a结果是在此研究的三种衍生物的最稳定的化合物。在鼠肝微粒体孵育后，[〜（18）f] 5a，b和[d _（2），〜（18）f] 5a的时间依赖性降解符合体内代谢的数据。此外，基于UPLC-MS / MS鉴定代谢物。

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