Wenz Jan, Arndt Felix, Samnick Samuel
Department of Nuclear Medicine, Interdisciplinary PET Center, Universitätsklinikum Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.
EJNMMI Radiopharm Chem. 2022 Mar 28;7(1):6. doi: 10.1186/s41181-022-00159-y.
The GMP-compliant production of radiopharmaceuticals has been performed using disposable units (cassettes) with a dedicated synthesis module. To expand this "plug 'n' synthesize" principle to a broader scope of modules we developed a pressure controlled setup that offers an alternative to the usual stepper motor controlled rotary valves. The new concept was successfully applied to the synthesis of N-methyl-[C]choline, L-S-methyl-[C]methionine and [C]acetate.
The target gas purification of cyclotron produced [C]CO and subsequent conversion to [C]MeI was carried out on a TRACERlab Fx C Pro module. The labelling reactions were controlled with a TRACERlab Fx FE module. With the presented modular principle we were able to produce N-methyl-[C]choline and L-S-methyl-[C]methionine by loading a reaction loop with neat N,N'-dimethylaminoethanol (DMAE) or an ethanol/water mixture of NaOH and L-homocysteine (L-HC), respectively and a subsequent reaction with [C]MeI. After 18 min N-methyl-[C]choline was isolated with 52% decay corrected yield and a radiochemical purity of > 99%. For L-S-methyl-[C]methionine the total reaction time was 19 min reaction, yielding 25% of pure product (> 97%). The reactor design was used as an exemplary model for the technically challenging [C]acetate synthesis. The disposable unit was filled with 1 mL MeMgCl (0.75 M) in tetrahydrofuran (THF) bevore [C]CO was passed through. After complete release of [C]CO the reaction mixture was quenched with water and guided through a series of ion exchangers (H, Ag and OH). The product was retained on a strong anion exchanger, washed with water and finally extracted with saline. The product mixture was acidified and degassed to separate excess [C]CO before dispensing. Under these conditions the total reaction time was 18 ± 2 min and pure [C]acetate (n = 10) was isolated with a decay corrected yield of 51 ± 5%.
Herein, we described a novel single use unit for the synthesis of carbon-11 labelled tracers for preclinical and clinical applications of N-methyl-[C]choline, L-S-methyl-[C]methionine and [C]acetate.
使用带有专用合成模块的一次性装置（盒式）来进行符合药品生产质量管理规范（GMP）的放射性药物生产。为了将这种“即插即合成”原理扩展到更广泛的模块范围，我们开发了一种压力控制装置，它为常用的步进电机控制旋转阀提供了一种替代方案。这个新概念已成功应用于N-甲基-[¹¹C]胆碱、L-S-甲基-[¹¹C]蛋氨酸和[¹¹C]乙酸盐的合成。
回旋加速器产生的[¹¹C]CO的目标气体净化以及随后转化为[¹¹C]MeI是在TRACERlab Fx C Pro模块上进行的。标记反应由TRACERlab Fx FE模块控制。通过所展示的模块化原理，我们能够通过分别向反应回路中装入纯的N,N'-二甲基氨基乙醇（DMAE）或NaOH与L-高半胱氨酸（L-HC）的乙醇/水混合物，随后与[¹¹C]MeI反应来生产N-甲基-[¹¹C]胆碱和L-S-甲基-[¹¹C]蛋氨酸。18分钟后，分离得到N-甲基-[¹¹C]胆碱，校正衰变后的产率为52%，放射化学纯度>99%。对于L-S-甲基-[¹¹C]蛋氨酸，总反应时间为19分钟，纯产物产率为25%（>97%）。该反应器设计被用作技术上具有挑战性的[¹¹C]乙酸盐合成的示例模型。在通入[¹¹C]CO之前，一次性装置中装入1mL四氢呋喃（THF）中的甲基氯化镁（MeMgCl，0.75M）。[¹¹C]CO完全释放后，反应混合物用水淬灭，并通过一系列离子交换剂（H、Ag和OH）。产物保留在强阴离子交换剂上，用水洗涤，最后用盐水萃取。在分配前，将产物混合物酸化并脱气以分离过量的[¹¹C]CO。在这些条件下，总反应时间为18±2分钟，分离得到纯的[¹¹C]乙酸盐（n = 10），校正衰变后的产率为51±5%。
在此，我们描述了一种新型一次性装置，用于合成用于N-甲基-[¹¹C]胆碱、L-S-甲基-[¹¹C]蛋氨酸和[¹¹C]乙酸盐临床前和临床应用的¹¹C标记示踪剂。
