Tshibangu Térence, Cawthorne Christopher, Serdons Kim, Pauwels Elin, Gsell Willy, Bormans Guy, Deroose Christophe M, Cleeren Frederik
Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 Box 821, 3000, Leuven, Belgium.
Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium.
EJNMMI Radiopharm Chem. 2020 Jan 29;5(1):4. doi: 10.1186/s41181-019-0084-1.
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 Ga eluted from a Ge/Ga generator. In contrast, F-tracers can be produced in large quantities allowing centralized production and distribution to distant PET centers. [F]AlF-NOTA-octreotide is a promising tracer that combines a straightforward AlF-based production procedure with excellent in vivo pharmacokinetics and specific tumor uptake, demonstrated in SSTR2 positive tumor mice. However, advancing towards clinical studies with [F]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 [F]AlF-NOTA-octreotide. In this study, we present the automated GMP production of [F]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 [F]AlF-NOTA-octreotide were assessed in healthy rats using μPET/MR.
The production process of [F]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, [F]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 [F]AlF-NOTA-octreotide allowing centralized production and shipment of the compound to remote PET centers. Further, the production process and quality control developed for [F]AlF-NOTA-octreotide is easily implementable in a clinical setting and the tracer is a potential clinical alternative for somatostatin directed Ga labeled peptides obviating the need for a Ge/Ga-generator. Finally, the favorable in vivo properties of [F]AlF-NOTA-octreotide in rats, with high and specific accumulation in SSTR2 expressing organs, supports clinical translation.
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生长抑素受体成像的当前金标准。尽管具有良好的成像特性，但从锗/镓发生器洗脱的镓产量较低，限制了它们在临床实践中的应用。相比之下，氟标记示踪剂可以大量生产，便于集中生产并分发给远处的PET中心。[F]AlF-NOTA-奥曲肽是一种很有前景的示踪剂，它结合了基于AlF的简单生产程序、出色的体内药代动力学和特异性肿瘤摄取，这已在SSTR2阳性肿瘤小鼠中得到证实。然而，推进[F]AlF-NOTA-奥曲肽的临床研究需要开发高效的自动化GMP生产工艺，并且需要进行额外的临床前研究以进一步评估[F]AlF-NOTA-奥曲肽的体内特性。在本研究中，我们展示了在Trasis AllinOne®放射性合成仪平台上[F]AlF-NOTA-奥曲肽的自动化GMP生产以及符合GMP的药品质量控制。此外，进行了放射性代谢物研究，并使用μPET/MR在健康大鼠中评估了[F]AlF-NOTA-奥曲肽的药代动力学和生物分布。
[F]AlF-NOTA-奥曲肽的生产工艺已通过三次验证生产运行得到验证，在合成结束时获得了最终批次活度为10.8±1.3 GBq的示踪剂，放射化学产率为26.1±3.6%（衰变校正），具有高放射化学纯度和稳定性（合成后6小时内高达96.3±0.2%），表观摩尔活度为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，[F]AlF-NOTA-奥曲肽在体内显示出高稳定性和良好的药代动力学，在大鼠中SSTR2表达器官中具有高特异性蓄积。
这种稳健的自动化生产工艺提供了高批次活度的[F]AlF-NOTA-奥曲肽，便于集中生产并将该化合物运往偏远的PET中心。此外，为[F]AlF-NOTA-奥曲肽开发的生产工艺和质量控制易于在临床环境中实施，并且该示踪剂是生长抑素导向的镓标记肽的潜在临床替代品，无需锗/镓发生器。最后，[F]AlF-NOTA-奥曲肽在大鼠中良好的体内特性，即在SSTR2表达器官中具有高特异性蓄积，支持其临床转化。
