以潜在临床应用为重点的[133La]LaCl3 生产可扩展性研究。

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR

EJNMMI Radiopharmacy and Chemistry Pub Date : 2024-08-15 DOI:10.1186/s41181-024-00292-w

Santiago Andrés Brühlmann, Martin Walther, Magdalena Kerstin Blei, Constantin Mamat, Klaus Kopka, Robert Freudenberg, Martin Kreller

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引用次数: 0

摘要

背景：近年来，α靶向治疗在临床上越来越受到重视，尤其是α发射体 225Ac 在临床发展中发挥着重要作用。然而，根据螯合系统的不同，与这种α发射放射性核素具有相似化学特性的真正诊断替代品尚未问世。事实上，推出与 225Ac 形成配对的诊断放射性核素的竞赛仍在进行中，而 133La 具有诱人的辐射特性，可以在这一领域占据一席之地。然而，为了将其应用于临床，需要扩大这种 PET 放射性核素的生产规模：结果：对最佳辐照参数、分离条件和详尽的产品特征进行了研究。在此框架内，质子辐照 2 小时、60 µA、18.7 MeV，在轰击结束时产生的 133La 放射性活度高达 10.7 GBq。此外，还测试了四种不同色谱树脂的性能，并提出了两种优化的纯化方法，耗时约 20 分钟，经衰变校正后，133La 回收率超过 98%。纯化结束时，放射性核素纯度和表观摩尔活度分别达到 99.5% 和 120 GBq/µmol。此外，还获得了 PSMA-617 和 mcp-M-PSMA 的定量复合物，摩尔活性高达 80 GBq/µmol。此外，这两种 133La 放射共轭物在血清中的稳定性都很高，分别超过 (98.5 ± 0.3) % 和 (99.20 ± 0.08)%，最长可达 24 小时。我们还进行了首次剂量估算，计算出 133La 应用于 350 至 750 MBq 的成像时，有效剂量仅为 2.1-4.4 mSv，与基于 18F 和 68Ga 的放射性药物相当：本文介绍了从辐射参数优化到临床剂量估算的 133La 生产总体研究。我们可以生产出 GBq 范围内的镧-133，并配制成[133La]LaCl3，其放射性标记质量和放射性核素纯度都很高。我们相信，增加 133La 的供应量将进一步促进基于大环或其他适合 225Ac 的螯合剂的放射性药物的开发。

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Scalability study on [133La]LaCl3 production with a focus on potential clinical applications

Background

In recent years, targeted alpha therapy has gained importance in the clinics, and in particular, the alpha-emitter ²²⁵Ac plays a fundamental role in this clinical development. Nevertheless, depending on the chelating system no real diagnostic alternative has been established which shares similar chemical properties with this alpha-emitting radionuclide. In fact, the race to launch a diagnostic radionuclide to form a matched pair with ²²⁵Ac is still open, and ¹³³La features attractive radiation properties to claim this place. However, in order to enable its translation into clinical use, upscaling of the production of this PET radionuclide is needed.

Results

A study on optimal irradiation parameters, separation conditions and an exhaustive product characterization was carried out. In this framework, a proton irradiation of 2 h, 60 µA and 18.7 MeV produced ¹³³La activities of up to 10.7 GBq at end of bombardment. In addition, the performance of four different chromatographic resins were tested and two optimized purification methods presented, taking approximately 20 min with a ¹³³La recovery efficiencies of over 98%, decay corrected. High radionuclide purity and apparent molar activity was proved, of over 99.5% and 120 GBq/µmol, respectively, at end of purification. Furthermore, quantitative complexation of PSMA-617 and mcp-M-PSMA were obtained with molar activities up to 80 GBq/µmol. In addition, both ¹³³La-radioconjugates offered high stability in serum, of over (98.5 ± 0.3)% and (99.20 ± 0.08)%, respectively, for up to 24 h. A first dosimetry estimation was also performed and it was calculated that an ¹³³La application for imaging with between 350 and 750 MBq would only have an effective dose of 2.1–4.4 mSv, which is comparable to that of ¹⁸F and ⁶⁸Ga based radiopharmaceuticals.

Conclusions

In this article we present an overarching study on ¹³³La production, from the radiation parameters optimization to a clinical dose estimation. Lanthanum-133 activities in the GBq range could be produced, formulated as [¹³³La]LaCl₃ with high quality regarding radiolabeling and radionuclide purity. We believe that increasing the ¹³³La availability will further promote the development of radiopharmaceuticals based on macropa or other chelators suitable for ²²⁵Ac.