Herein, we present the syntheses and characterization of a new undecadendate chelator, H₄py4pa, and its bifunctional analog H₄py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H₄py4pa possesses excellent affinity for ²²⁵Ac (α, t_1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10^–6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H₄py4pa with large metal ions, lanthanum (La³⁺), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for ²²⁵Ac to enable a series of nonradioactive chemical studies. In line with the ¹H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]⁻ anion possessed a high degree of symmetry, and the La³⁺ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]⁻ complex also demonstrated a superb thermodynamic stability (log K_[La(py4pa)]^– ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K_[La(DOTA)]^– ∼ 24.25, pLa = 19.2) or H₂macropa (log K_{[La(macropa)]}^– = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H₄py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

中文翻译：

---

225Ac-H4py4pa 用于靶向 Alpha 疗法

在此，我们介绍了一种新的十一烷基螯合剂 H ₄ py4pa 及其双功能类似物 H ₄ py4pa-苯基-NCS的合成和表征，它们与靶向 HER2+ 癌症的单克隆抗体曲妥珠单抗偶联。H ₄ py4pa 对²²⁵ Ac (α, t _1/2 = 9.92 d)具有出色的亲和力，用于靶向 α 疗法 (TAT)，其中在环境温度、pH = 7、10 ^–6 M 下30 分钟内实现了定量放射性标记产量螯合剂浓度，导致复合物在小鼠血清中高度稳定至少 9 天。研究 H ₄ py4pa 与大金属离子、镧 (La ³⁺) 是镧系元素中最大的非放射性金属，被用作²²⁵ Ac的替代物，以进行一系列非放射性化学研究。与¹ H NMR 谱一致，[La(py4pa)] ^-阴离子的 DFT（密度泛函理论）计算结构具有高度对称性，La ³⁺离子由两对不同的吡啶甲酸酯固定武器。此外，[La（上py4pa）] ^-复合物也表现出了极好的热力学稳定性（日志ķ _{[La（上py4pa）]} ^-的那些相比DOTA（的〜20.33，PLA = 21.0）日志ķ _{[拉（DOTA）]} ^- 〜24.25, pLa = 19.2) 或 H ₂macropa (log K _{[La(macropa)]} ^– = 14.99, pLa ∼ 8.5)。此外，双功能 py4pa 前体提供的功能多功能性允许通过直接亲核取代轻松掺入各种接头进行生物偶联。在这项工作中，一个短的苯基-NCS接头被掺入以将 H ₄ py4pa连接到曲妥珠单抗。放射性标记研究、体外血清稳定性和动物研究与 DOTA-苄基-曲妥珠单抗同时进行。两者都显示出优异的体内稳定性和肿瘤特异性。