Gallium-68 labeled synthetic somatostatin analogs for PET/CT imaging are the current gold standard for somatostatin receptor imaging in neuroendocrine tumor patients. Despite good imaging properties, their use in clinical practice is hampered by the low production levels of 68Ga eluted from a 68Ge/68Ga generator. In contrast, 18F-tracers can be produced in large quantities allowing centralized production and distribution to distant PET centers. [18F]AlF-NOTA-octreotide is a promising tracer that combines a straightforward Al18F-based production procedure with excellent in vivo pharmacokinetics and specific tumor uptake, demonstrated in SSTR2 positive tumor mice. However, advancing towards clinical studies with [18F]AlF-NOTA-octreotide requires the development of an efficient automated GMP production process and additional preclinical studies are necessary to further evaluate the in vivo properties of [18F]AlF-NOTA-octreotide. In this study, we present the automated GMP production of [18F]AlF-NOTA-octreotide on the Trasis AllinOne® radio-synthesizer platform and quality control of the drug product in accordance with GMP. Further, radiometabolite studies were performed and the pharmacokinetics and biodistribution of [18F]AlF-NOTA-octreotide were assessed in healthy rats using μPET/MR. The production process of [18F]AlF-NOTA-octreotide has been validated by three validation production runs and the tracer was obtained with a final batch activity of 10.8 ± 1.3 GBq at end of synthesis with a radiochemical yield of 26.1 ± 3.6% (dc), high radiochemical purity and stability (96.3 ± 0.2% up to 6 h post synthesis) and an apparent molar activity of 160.5 ± 75.3 GBq/μmol. The total synthesis time was 40 ± 3 min. Further, the quality control was successfully implemented using validated analytical procedures. Finally, [18F]AlF-NOTA-octreotide showed high in vivo stability and favorable pharmacokinetics with high and specific accumulation in SSTR2-expressing organs in rats. This robust and automated production process provides high batch activity of [18F]AlF-NOTA-octreotide allowing centralized production and shipment of the compound to remote PET centers. Further, the production process and quality control developed for [18F]AlF-NOTA-octreotide is easily implementable in a clinical setting and the tracer is a potential clinical alternative for somatostatin directed 68Ga labeled peptides obviating the need for a 68Ge/68Ga-generator. Finally, the favorable in vivo properties of [18F]AlF-NOTA-octreotide in rats, with high and specific accumulation in SSTR2 expressing organs, supports clinical translation.

中文翻译：

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[18F] AlF-NOTA-奥曲肽的GMP自动化生产。

用于PET / CT成像的镓68标记的合成生长抑素类似物是神经内分泌肿瘤患者中生长抑素受体成像的当前金标准。尽管具有良好的成像性能，但从68Ge / 68Ga发生器洗脱出的68Ga的生产水平低，阻碍了它们在临床实践中的使用。相反，可以大量生产18F示踪剂，从而可以集中生产并分配到遥远的PET中心。[18F] AlF-NOTA-奥曲肽是一种有前途的示踪剂，将基于Al18F的直接生产程序与出色的体内药代动力学和特异性肿瘤吸收相结合，已在SSTR2阳性肿瘤小鼠中证实。然而，推进[18F] AlF-NOTA-奥曲肽临床研究需要开发一种有效的自动GMP生产工艺，并且有必要进行额外的临床前研究以进一步评估[18F] AlF-NOTA-奥曲肽的体内特性。在这项研究中，我们介绍了在TrasisAllinOne®放射合成仪平台上自动生产[18F] AlF-NOTA-奥曲肽的GMP，并根据GMP对药品进行质量控制。此外，进行了放射性代谢研究，并使用μPET/ MR在健康大鼠中评估了[18F] AlF-NOTA-奥曲肽的药代动力学和生物分布。[18F] AlF-NOTA-奥曲肽的生产过程已通过三个验证生产运行进行了验证，在合成结束时获得了示踪剂，其最终批处理活性为10.8±1.3 GBq，放射化学收率为26。1±3.6％（dc），高放射化学纯度和稳定性（合成后最多6小时达96.3±0.2％），表观摩尔活性为160.5±75.3 GBq /μmol。总合成时间为40±3分钟。此外，使用经过验证的分析程序成功实施了质量控制。最后，[18F] AlF-NOTA-奥曲肽显示出高的体内稳定性和良好的药代动力学，并在大鼠的表达SSTR2的器官中具有高且特异性的积累。这种强大而自动化的生产过程可提供[18F] AlF-NOTA-奥曲肽的高批处理活性，从而允许将化合物集中生产并将其运输到远程PET中心。进一步，为[18F] AlF-NOTA-奥曲肽开发的生产工艺和质量控制可在临床环境中轻松实施，而示踪剂是生长抑素导向的68Ga标记肽的潜在临床替代品，从而无需68Ge / 68Ga发生器。最后，[18F] AlF-NOTA-奥曲肽在大鼠中具有良好的体内特性，在表达SSTR2的器官中具有高特异性积累，支持临床翻译。