The synthesis and evaluation of the newest generation of our DFO2 chelator family—DFO2K—is described. DFO2K was designed with a simple synthetic route to access different bifunctional derivatives, with each derivative having similar metal ion coordination spheres and high denticity (up to 12 coordinate) to ensure stable coordination of zirconium-89. The high denticity could potentially enhance stability with other large oxophilic radiometals. Zirconium-89 is the most popular radionuclide to pair with large macromolecules such as antibodies (immunoPET) for positron emission tomography applications. Although clinically successful, the stability of the “gold standard” chelator desferrioxamine B (DFO) can be improved as significant bone uptake is observed in animal models, despite no obvious stability issues in humans. Following the synthesis of DFO2K we assessed its radiolabeling efficiency with zirconium-89 and compared with DFO, which revealed rapid and nearly identical radiolabeling kinetics to DFO. The resultant [⁸⁹Zr]Zr–DFO2K complex showed improved stability over [⁸⁹Zr]Zr–DFO in different in vitro stability assays such as hydroxyapatite and 1000-fold molar excess EDTA challenges. Furthermore, biodistribution studies of the non-bifunctional chelators in healthy mice showed that [⁸⁹Zr]Zr–DFO2K had a similar distribution profile and clearance to [⁸⁹Zr]Zr–DFO. The bifunctional derivative p-SCN–Ph–DFO2K was conjugated to a non-specific human IgG antibody and evaluated after 2 weeks circulating in healthy female CD1 mice. Mice administered [⁸⁹Zr]Zr–DFO2K–IgG showed substantially lower bone uptake in PET-CT images than [⁸⁹Zr]Zr–DFO–IgG, with PET ROI data and ex vivo biodistribution revealing a statistically significantly lower bone uptake for DFO2K. Overall, owing to its high denticity, ease of synthesis, improved solubility over DFO2 and DFO2p, and stable chelation of zirconium-89, DFO2K appears to be an improved alternative chelator to DFO for zirconium-89 chelation.

中文翻译：

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双功能 DFO2K 的合成和评估：具有理想的锆 89 螯合性能的模块化螯合剂


描述了我们最新一代 DFO2 螯合剂家族 DFO2K 的合成和评估。 DFO2K通过简单的合成路线设计来获得不同的双功能衍生物，每种衍生物具有相似的金属离子配位球和高齿数（高达12配位），以确保锆89的稳定配位。高密度可能会增强其他大型亲氧放射性金属的稳定性。 Zircium-89 是最常用的放射性核素，可与大分子（例如抗体 (immunoPET)）配对，用于正电子发射断层扫描应用。尽管在临床上取得了成功，但“金标准”螯合剂去铁胺 B (DFO) 的稳定性可以得到改善，因为在动物模型中观察到显着的骨吸收，尽管在人类中没有明显的稳定性问题。合成 DFO2K 后，我们用 zircium-89 评估了其放射性标记效率，并与 DFO 进行了比较，结果显示与 DFO 具有快速且几乎相同的放射性标记动力学。在不同的体外稳定性测定（例如羟基磷灰石和 1000 倍摩尔过量 EDTA 挑战）中，所得的 [ ⁸⁹ Zr]Zr-DFO2K 复合物表现出比 [ ⁸⁹ Zr]Zr-DFO 更高的稳定性。此外，健康小鼠中非双功能螯合剂的生物分布研究表明，[ ⁸⁹ Zr]Zr–DFO2K 与 [ ⁸⁹ Zr]Zr–DFO 具有相似的分布特征和清除率。双功能衍生物 p-SCN-Ph-DFO2K 与非特异性人 IgG 抗体缀合，并在健康雌性 CD1 小鼠中循环两周后进行评估。 给予 [ ⁸⁹ Zr]Zr–DFO2K–IgG 的小鼠在 PET-CT 图像中显示出比 [ ⁸⁹ Zr]Zr–DFO–IgG 显着降低的骨摄取（PET ROI 数据和 ex）体内生物分布显示 DFO2K 的骨吸收具有统计学上显着的降低。总体而言，由于其高密度、易于合成、比 DFO2 和 DFO2p 更高的溶解度以及与 89 锆的稳定螯合，DFO2K 似乎是用于 89 锆螯合的 DFO 的改进替代螯合剂。