Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States.
Chemistry Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States.
Inorg Chem. 2021 Jan 18;60(2):623-632. doi: 10.1021/acs.inorgchem.0c02432. Epub 2020 Nov 19.
Actinium-225 (Ac) is an excellent candidate for targeted radiotherapeutic applications for treating cancer, because of its 10-day half-life and emission of four high-energy α particles. To harness and direct the energetic potential of actinium, strongly binding chelators that remain stable during biological targeting must be developed. Unfortunately, controlling chelation for actinium remains challenging. Actinium is the largest +3 cation on the periodic table and has a 6d5f electronic configuration, and its chemistry is relatively unexplored. Herein, we present theoretical work focused on improving the understanding of actinium bonding with macrocyclic chelating agents as a function of (1) macrocycle ring size, (2) the number and identity of metal binding functional groups, and (3) the length of the tether linking the metal binding functional group to the macrocyclic backbone. Actinium binding by these chelators is presented within the context of complexation with DOTA, the most relevant Ac binding agent for contemporary radiopharmaceutical applications. The results enabled us to develop a new strategy for actinium chelator design. The approach is rooted in our identification that Ac-chelation chemistry is dominated by ionic bonding interactions and relies on (1) maximizing electrostatic interactions between the metal binding functional group and the Ac cation and (2) minimizing electronic repulsion between negatively charged actinium binding functional groups. This insight will provide a foundation for future innovation in developing the next generation of multifunctional actinium chelators.
锕-225（Ac）是治疗癌症的靶向放射治疗应用的极佳候选物，因为它的半衰期为 10 天，并且发射四个高能α粒子。为了利用和引导锕的能量潜力，必须开发在生物靶向过程中保持稳定的强结合螯合剂。不幸的是，控制锕的螯合仍然具有挑战性。锕是元素周期表上最大的+3 阳离子，具有 6d5f 电子构型，其化学性质相对未知。在此，我们提出了理论工作，重点是改善对锕与大环螯合剂结合的理解，作为（1）大环环尺寸，（2）金属结合功能基团的数量和身份以及（3）将金属结合功能基团连接到大环主链的键的长度的函数。这些螯合剂与锕的结合在与 DOTA 络合的背景下提出，DOTA 是当前放射性药物应用中与 Ac 结合最相关的配体。结果使我们能够开发出一种新的锕螯合剂设计策略。该方法的基础是我们确定 Ac-螯合化学主要由离子键相互作用控制，并依赖于（1）最大程度地增强金属结合功能基团与 Ac 阳离子之间的静电相互作用，以及（2）最小化带负电荷的锕结合功能基团之间的电子排斥作用。这一见解将为未来开发下一代多功能锕螯合剂提供基础。
