Recent advancements in positron emission tomograph (PET) using prostate specific membrane antigen (PSMA)-targeted radiopharmaceuticals have changed the standard of care for prostate cancer patients by providing more accurate information during staging of primary and recurrent disease. [68Ga]Ga-P16-093 is a new PSMA-PET radiopharmaceutical that demonstrated superior imaging performance in recent head-to-head studies with [68Ga]Ga-PSMA-11. To improve the availability of this new PSMA PET imaging agent, [18F]AlF-P16-093 was developed. The 18F-analog [18F]AlF-P16-093 has been synthesized manually at low activity levels using [18F]AlF2+ and validated in pre-clinical models. This work reports the optimization of the production of > 15 GBq of [18F]AlF-P16-093 using a custom automated synthesis platform. The sensitivity of the radiochemical yield of [18F]AlF-P16-093 to reaction parameters of time, temperature and reagent amounts was investigated using a custom automated system. The automated system is a low-cost, cassette-based system designed for 1-pot syntheses with flow-controlled solid phase extraction (SPE) workup and is based on the Raspberry Pi Zero 2 microcomputer/Python3 ecosystem. The optimized none-decay-corrected yield was 52 ± 4% (N = 3; 17.5 ± 2.2 GBq) with a molar activity of 109 ± 14 GBq/µmole and a radiochemical purity of 98.6 ± 0.6%. Run time was 30 min. A two-step sequence was used: SPE-purified [18F]F− was reacted with 80 nmoles of freeze-dried AlCl3·6H2O at 65 °C for 5 min followed by reaction with 160 nmoles of P16-093 ligand at 40 °C for 4 min in a 1:1 mixture of ethanol:0.5 M pH 4.5 NaOAc buffer. The mixture was purified by SPE (> 97% recovery). The final product formulation (5 mM pH 7 phosphate buffer with saline) exhibited a rate of decline in radiochemical purity of ~ 1.4%/h which was slowed to ~ 0.4%/h when stored at 4 °C. The optimized method using a custom automated system enabled the efficient (> 50% none-decay-corrected yield) production of [18F]AlF-P16-093 with high radiochemical purity (> 95%). The method and automation system are simple and robust, facilitating further clinical studies with [18F]AlF-P16-093.

中文翻译：

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在定制自动化放射合成平台上优化和扩大 PSMA 显像剂 [18F]AlF-P16-093 的生产

使用前列腺特异性膜抗原 (PSMA) 靶向放射性药物的正电子发射断层扫描 (PET) 的最新进展通过在原发性疾病和复发性疾病分期期间提供更准确的信息，改变了前列腺癌患者的护理标准。[68Ga]Ga-P16-093 是一种新型 PSMA-PET 放射性药物，在最近与 [68Ga]Ga-PSMA-11 的头对头研究中表现出卓越的成像性能。为了提高这种新型 PSMA PET 成像剂的可用性，开发了 [18F]AlF-P16-093。18F-类似物[18F]AlF-P16-093是使用[18F]AlF2+在低活性水平下手动合成的，并在临床前模型中进行了验证。这项工作报告了使用定制自动化合成平台优化生产 > 15 GBq 的 [18F]AlF-P16-093。使用定制的自动化系统研究了[ 18 F]AlF-P16-093的放射化学产率对时间、温度和试剂量等反应参数的敏感性。该自动化系统是一种低成本、基于盒的系统，设计用于具有流量控制固相萃取 (SPE) 后处理的一锅合成，并且基于 Raspberry Pi Zero 2 微型计算机/Python3 生态系统。优化的非衰变校正产率为 52 ± 4% (N = 3; 17.5 ± 2.2 GBq)，摩尔活度为 109 ± 14 GBq/μmole，放射化学纯度为 98.6 ± 0.6%。运行时间为 30 分钟。使用两步顺序：SPE 纯化的 [18F]F− 与 80 nmole 冻干 AlCl3·6H2O 在 65 °C 反应 5 分钟，然后与 160 nmole P16-093 配体在 40 °C 反应在 1:1 乙醇:0.5 M pH 4.5 NaOAc 缓冲液混合物中反应 4 分钟。通过 SPE 纯化混合物（> 97% 回收率）。最终产品配方（含盐水的 5 mM pH 7 磷酸盐缓冲液）的放射化学纯度下降速率为约 1.4%/h，在 4 °C 下储存时减慢至约 0.4%/h。使用定制自动化系统的优化方法能够高效（> 50% 非衰变校正产率）生产具有高放射化学纯度 (> 95%) 的 [18F]AlF-P16-093。该方法和自动化系统简单而稳健，有利于[18F]AlF-P16-093的进一步临床研究。