Chelation strategies for s-, p-, and f-block radionuclides for targeted alpha therapy

项目摘要 靶向α治疗（达特）采用α放射性核素结合生物靶向 载体来摧毁肿瘤细胞。α粒子由于其高线性能量转移而非常有效， 使得这些类型的放射性发射极有希望用于根除癌细胞。疗效 最近FDA批准α发射器223 RaCl 2用于治疗证明了α粒子疗法的有效性。 前列腺癌骨转移的患者。然而，由于223 RaCl 2是达特的非靶向形式，因此它 不能以其目前的形式用于治疗软组织肿瘤或内脏转移。为了治疗这些形式 对于癌症，α放射性核素需要与生物靶向载体（如抗体）结合， 和肽，其以高特异性和亲和力与在癌症中选择性过表达的受体结合 细胞设计这种靶向构建体的关键挑战在于需要双功能螯合剂， 试剂，与靶向载体共价结合并与其形成非常稳定的复合物的配体 体内的阿尔法放射性金属双官能螯合剂充当所述双官能螯合剂之间的必要连接。 α发射体和靶向载体，从根本上实现了靶向达特的概念。的发展 然而，对于达特有用的放射性核素的有效双功能螯合剂已经受到 这些金属离子的配位化学不完善。在本项目中，我们将研究 化学和设计新的配体的金属离子是有价值的达特。这些基本的螯合作用 研究将推动未来的努力，设计新的双功能螯合剂，使目标达特的使用， 诊所我们的努力将集中在三个金属离子，跨越s-，p-和f-块的周期表。在 具体目标1，我们将探索Ra 2+的配位化学，并设计新的螯合剂， 这个离子。我们将追求大的大环，构象约束作为这个离子的潜在配体。 这些努力将促进FDA批准的α发射器223 Ra用于软组织或 内脏转移具体目标2将重点关注p区离子Bi 3+。放射性核素213 Bi是一种短寿命的α- 已在临床试验中评估的发射器。我们对这种离子的设计策略将依赖于它对 氮给体原子和由其立体活性6S 2孤对产生的各向异性配位球。在 具体目标3，将开发230 U的螯合方法。这种放射性核素具有理想的性能， 达特，但尚未用于此应用程序。我们努力开发UO 22+离子的配体， 该元素在水溶液中的稳定形式将使其治疗实施成为可能。我们将设计配体 结合在UO 22+阳离子的赤道平面上，并提供外层氢键供体， 与末端氧代配体相互作用。总的来说，本项目中的基本配位化学将 使得这些发射α的放射性核素可用于治疗应用。

PROJECT SUMMARY Targeted alpha therapy (TAT) employs alpha-emitting radionuclides in conjunction with biological targeting vectors to destroy tumor cells. Alpha particles are extremely potent due to their high linear energy transfer, rendering these types of radioactive emissions highly promising for the eradication of cancer cells. The efficacy of alpha particle therapy is evidenced by the recent FDA approval of the alpha emitter 223RaCl2 for the treatment of prostate cancer patients with bone metastases. Because 223RaCl2 is a non-targeted form of TAT, however, it cannot be used in its current form to treat soft tissue tumors or visceral metastases. In order to treat these forms of cancer, alpha-emitting radionuclides need to be conjugated to biological targeting vectors, such as antibodies and peptides, that bind with high specificity and affinity to receptors that are selectively overexpressed in cancer cells. A key challenge for the design of such targeted constructs lies in the need for a bifunctional chelating agent, a ligand that is covalently bound to the targeting vector and that forms exceedingly stable complexes with the alpha-emitting radiometals in vivo. The bifunctional chelator acts as the requisite attachment between the alpha emitter and targeting vector, fundamentally enabling the concept of targeted TAT. The development of effective bifunctional chelators for radionuclides that are useful for TAT, however, has been hindered by the poorly established coordination chemistry of these metal ions. In this project, we will study the coordination chemistry of and design new ligands for metal ions that are valuable for TAT. These fundamental chelation studies will drive future efforts to design new bifunctional chelating agents, enabling the use of targeted TAT in the clinic. Our efforts will focus on three metal ions, spanning the s-, p-, and f-block of the periodic table. In Specific Aim 1, we will probe the coordination chemistry of Ra2+ and design new chelators that can stably retain this ion. We will pursue large macrocycles that are conformationally constrained as potential ligands for this ion. These efforts will facilitate the implementation of the FDA-approved alpha-emitter 223Ra for use in soft tissue or visceral metastases. Specific Aim 2 will focus on the p-block ion Bi3+. The radionuclide 213Bi is a short-lived alpha- emitter that has been evaluated in clinical trials. Our design strategies for this ion will rely on its high affinity for nitrogen donor atoms and the anisotropic coordination sphere resulting from its stereoactive 6s2 lone pair. In Specific Aim 3, chelation approaches for 230U will be developed. This radionuclide has ideal properties for use in TAT but has not yet been used for this application. Our efforts to develop ligands for the UO22+ ion, the most stable form of this element in aqueous solution, will enable its therapeutic implementation. We will design ligands that bind in the equatorial plane of the UO22+ cation and provide outer-sphere hydrogen bond donors for interacting with the terminal oxo ligands. Collectively, the fundamental coordination chemistry in this project will render these alpha-emitting radionuclides accessible for therapeutic applications.