Development of an automated, GMP compliant FASTlabTM radiosynthesis of [18 F]GE-179 for the clinical study of activated NMDA receptors,Journal of Labelled Compounds and Radiopharmaceuticals

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Development of an automated, GMP compliant FASTlabTM radiosynthesis of [18 F]GE-179 for the clinical study of activated NMDA receptors
Journal of Labelled Compounds and Radiopharmaceuticals ( IF 0.9 ) Pub Date : 2020-03-05 , DOI: 10.1002/jlcr.3831
Imtiaz Khan ₁ , Tom Christian Berg ₂ , Jane Brown ₁ , Rajiv Bhalla ₁ , Anthony Wilson ₁ , Andrew Black ₁ , Graeme McRobbie ₁ , James Nairne ₁ , Andreas Olsson ₂ , William Trigg ₁

Affiliation

N-(2-chloro-5-(S-2-[18 F]fluoroethyl)thiophenyl)-N'-(3-thiomethylphenyl)-N'-methylguanidine, ([18 F]GE-179), has been identified as a promising positron emission tomography (PET) ligand for the intra-channel phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The radiosynthesis of [18 F]GE-179 at low radioactivity levels has been previously reported.1 However, the manufacture of a GMP compliant product at high radioactivity levels was required for clinical studies. We describe the development of a process using the GE FASTlabTM radiosynthesis platform coupled with HPLC purification. The radiosynthesis is a two-step process, involving the nucleophilic fluorination of ethylene ditosylate, 11, followed by alkylation to the deprotonated thiol precursor, N-(2-chloro-5-thiophenol)-N'-(3-thiomethylphenyl)-N'-methyl guanidine, 8. The crude product was purified by semi-preparative HPLC to give the formulated product in an activity yield (AY) of 7 ± 2% (n = 15) with a total synthesis time of 120 minutes. The radioactive concentration (RAC) and radiochemical purity (RCP) were 328 ± 77 MBq/mL and 96.5 ± 1% respectively and the total chemical content was 2 ± 1 μg. The final formulation volume was 14 mL. The previously described radiosynthesis of [18 F]GE-179 was successfully modified to deliver an process on the FASTlabTM that allows the manufacture of a GMP quality product from high starting radioactivitity (up to 80 GBq) and delivers a product suitable for clinical use.

中文翻译：

开发自动化、符合 GMP 的 FASTlabTM 放射合成 [18 F]GE-179，用于激活 NMDA 受体的临床研究

N-(2-氯-5-(S-2-[18 F]氟乙基)噻吩基)-N'-(3-硫甲基苯基)-N'-甲基胍，([18 F]GE-179)，已被鉴定作为 N-甲基-D-天冬氨酸 (NMDA) 受体通道内苯环己哌啶 (PCP) 结合位点的有前途的正电子发射断层扫描 (PET) 配体。先前已报道过低放射性水平的 [18 F]GE-179 的放射合成。1 然而，临床研究需要生产高放射性水平的符合 GMP 的产品。我们描述了使用 GE FASTlabTM 放射合成平台与 HPLC 纯化相结合的工艺开发。放射合成是一个两步过程，涉及二甲苯磺酸乙二酯 11 的亲核氟化，然后烷基化为去质子化的硫醇前体 N-(2-氯-5-苯硫酚)-N'-(3-硫甲基苯基)-N '-甲基胍，8。粗产物通过半制备型 HPLC 纯化，得到活性产率 (AY) 为 7 ± 2% (n = 15) 的配制产物，总合成时间为 120 分钟。放射性浓度（RAC）和放射化学纯度（RCP）分别为328±77MBq/mL和96.5±1%，总化学含量为2±1μg。最终制剂体积为14mL。先前描述的 [18 F]GE-179 放射合成经过成功修改，可在 FASTlabTM 上提供一种工艺，允许从高起始放射性（高达 80 GBq）生产 GMP 质量的产品，并提供适合临床使用的产品。

更新日期：2020-03-05

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