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首页> 外文OA文献 >In Vivo Biodistribution of No-Carrier-Added 6-F-18-Fluoro-3, 4-Dihydroxy-L-Phenylalanine (F-18-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added F-18-DOPA, Prepared by Conventional Electrophilic Substitution
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In Vivo Biodistribution of No-Carrier-Added 6-F-18-Fluoro-3, 4-Dihydroxy-L-Phenylalanine (F-18-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added F-18-DOPA, Prepared by Conventional Electrophilic Substitution

机译：与载体添加的F-18相比，通过新的亲核取代方法产生的无载体添加的6-F-18-Fluoro-3、4-二羟基-L-苯丙氨酸（F-18-DOPA）的体内生物分布。 -DOPA，通过常规亲电取代制备

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A novel synthetic approach to 6-F-18-fluoro-3,4-dihydroxy-L-phenylalanine (F-18-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added F-18-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method, involving an electrophilic substitution of a trialkylstannane precursor with F-18(2). We performed a direct comparison of high-and lowspecific-activity F-18-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of F-18-DOPA. Methods: F-18-DOPA was produced via the novel synthesis method, yielding F-18-DOPA-H with a high specific activity (35,050 +/- 4,000 GBq/mmol). This product was compared in several experiments with conventional F-18-DOPA-L with a low specific activity (11 +/- 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0 degrees C and 37 degrees C and at 37 degrees C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of F-18-DOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft. Results: At 37 degrees C, the uptake of both F-18-DOPA-H and F-18-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0 degrees C, the uptake of F-18-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of F-18-DOPA-H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of F-18-DOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of F-18-DOPA-H and F-18-DOPA-L in carbidopapretreated mice. Conclusion: The advantages of the novel synthesis of F-18-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active F-19-DOPA. F-18-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than F-18-DOPA-L.
机译：一种6-F-18-氟-3,4-二羟基-L-苯丙氨酸（F-18-DOPA）的新颖合成方法，涉及用不添加载体的F-18-氟化物对二芳基碘鎓盐前体进行亲核取代所得到的产物的比活度比常规合成方法的产物高3个数量级，涉及用F-18（2）亲电子取代三烷基锡烷前体。我们在神经内分泌肿瘤模型中进行了高和低特异性活性F-18-DOPA的直接比较，以确定这种特定活性的差异是否对F-18-DOPA的生物学行为和成像特性有影响。方法：通过新颖的合成方法生产F-18-DOPA，得到具有高比活度（35,050 +/- 4,000 GBq / mmol）的F-18-DOPA-H。在几次实验中，将该产物与具有低比活性（11 +/- 2 GBq / mmol）的常规F-18-DOPA-L进行了比较。在存在涉及F-18-DOPA摄取机制的蛋白质的药理抑制剂的情况下，在0摄氏度和37摄氏度以及37摄氏度下进行了人胰腺神经内分泌肿瘤细胞系BON-1的体外蓄积实验。在携带BON-1肿瘤异种移植的无胸腺裸鼠中进行小动物PET实验。结果：在37°C下，在BON-1细胞中进行60分钟的积累实验期间，F-18-DOPA-H和F-18-DOPA-L的摄取均无显着差异。在0摄氏度时，F-18-DOPA-L的吸收显着降低，而较低的温度不会改变F-18-DOPA-H的吸收。药理抑制剂卡比多巴和丁苯那嗪在60分钟累积实验中也显示出两种类型的F-18-DOPA之间的差异作用。小动物PET实验未显示在卡比多巴预处理的小鼠中F-18-DOPA-H和F-18-DOPA-L的分布和代谢没有任何显着差异。结论：F-18-DOPA新颖合成的优点是依赖于二芳基碘鎓盐前体的亲核氟化，与传统的亲电子方法相比，其合成方法简单，并且可降低给药量，具有药理活性的F-19-DOPA。尽管注入的物质质量比F-18-DOPA-L小3个数量级，但F-18-DOPA-H在神经内分泌肿瘤的体内模型中显示出可比的成像特性。

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