Abstract

Purpose

¹²³I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, ¹²³I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize ¹²³I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.

Materials and methods

¹²³I-MAPi was prepared in a single step via ¹²³I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of ¹²³I-MAPi in a small cell lung cancer model.

Results

¹²³I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq µmol⁻¹. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation.

Conclusions

Here, we have developed an improved radiosynthesis of ¹²³I-MAPi, an Auger theranostic agent. This process was achieved using a single step, ¹²³I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. ¹²³I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.

中文翻译：

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改进螺旋治疗诊断剂 123I-MAPi 的放射合成

 抽象的

 目的

¹²³ I-MAPi 是一种新型 PARP1 靶向俄歇放射治疗药物，已在临床前神经胶质瘤模型中显示出有希望的结果。目前， ¹²³ I-MAPi 是采用多步合成法合成的，产量适中，摩尔活性 (MA) 较低，限制了将该技术应用于高剂量人类研究的能力。因此，需要新的方法以高活性产率（AY）合成¹²³ I-MAPi 并改进 MA，以促进临床转化和多中心试验。

 材料和方法

¹²³ I-MAPi 通过相应三丁基锡烷前体的¹²³ I-碘代丁酰化一步制备。体外内化测定、亚细胞分级和共聚焦显微镜用于评估¹²³ I-MAPi 在小细胞肺癌模型中的性能。

 结果

¹²³ I-MAPi 由相应的锡烷前体一步合成，AY 为 45 ± 2%，MA 为 11.8 ± 4.8 GBq µ mol ^-1 。体外 LX22 细胞显示出快速内化（5 分钟），通过亚细胞分级分离测定，主要在细胞膜、细胞核和染色质中发现积累。

 结论

在这里，我们开发了一种改进的¹²³ I-MAPi（一种俄歇治疗诊断剂）的放射合成。该过程是使用一步¹²³ I-碘脱锡烷基化反应从良好的 AY 和 MA 中相应的锡烷前体实现的。 ¹²³ I-MAPi 在小细胞肺癌模型中进行了体外评估，显示出高 PARP 表达、快速内化和高核摄取。