Novel chemistry to improve the biostability of organo-astatine bonds in alpha-emitting radiopharmaceutical therapeutics

摘要/摘要 在现存的为数不多的发射阿尔法的放射性核素中，~(211)At是最有希望发射阿尔法的放射性核素之一 放射性核素，因为它的物理和化学性质与阿尔法辐射完全匹配 放射药物疗法(阿尔法-RPTS)，用于治疗其他无法治愈的肿瘤。然而，在 药物靶向构建体体内释放~(211)At降低了治疗效果，但增加了 对正常组织的毒性，是实现~(211)At-α-RPTS真正潜力的最大障碍。这 该提案直接解决了尚未得到满足的关键需求，即开发新的化学来改进有机-司他丁 键合稳定，防止其在体内释放。碳-卤键强度与卤素成反比 作为最大的卤素，碳原子(C-At)的键合强度最弱，这使得它 在体内更容易发生氧化脱卤化。目前，大多数~(211)At-共轭方法使用C-At键 结果是生物稳定性很差。或者，使用B-At键，它比 C-At键，是提高~(211)At-α-RPTS体内稳定性的有效策略。因此，我们建议 研究以前未被探索过的唯一适合作为药剂的硼杂原子环系 开发生物稳定的~(211)At-α-RPTS。这些环系已经建立了卤化化学 适用于环体系中硼或碳位置的取代，每个位置都提供唯一的 用于增强稳定性和使~(211)At-Re~(211)At的正交路径成为可能的性质--放射性。在这份提案中，我们 将系统地研究取代硼杂环的化学，以开发新的方法 用于211At-无线电传输，并将基础科学发现转化为可应用的技术，由 用生物稳定的小分子~(211)At-α-RPT展示“概念证明”。

Abstract/Summary Of the few alpha-emitting radionuclides that exist, astatine-211 (211At) is one of the most promising alpha-emitting radionuclides, because its physical and chemical properties are perfectly matched for alpha-emitting radiopharmaceutical therapeutics (alpha-RPTs) used for treatment of otherwise incurable tumors. However, the in vivo release of 211At from pharmacological targeting constructs diminishes therapeutic efficacy while increasing toxicity to normal tissues, and is the single biggest obstacle for realizing the true potential of 211At-alpha-RPTs. This proposal directly addresses the critical unmet need to develop novel chemistry for improving organo-astatine bond stability to prevent its release in vivo. The carbon-halogen bond strength is inversely related with halogen size, and as the largest halogen, the bond strength of carbon-astatine (C-At) is the weakest, which makes it more vulnerable to oxidative dehalogenation in vivo. Currently, most 211At-conjugation methods use C-At bonds and as a result have poor biostability. Alternatively, using boron-astatine (B-At) bonds, which are stronger than C-At bonds, is an effective strategy to improve the in vivo stability of 211At-alpha-RPTs. Therefore, we propose to investigate previously unexplored boron hetero-atom ring systems that are uniquely well-suited as pharmacons to develop biologically stable 211At-alpha-RPTs. These ring systems have established halogenation chemistry adaptable for astatine-substitution at boron or carbon positions in ring systems, each providing unique properties for enhancing stability and enable orthogonal routes for 211At-radioastatination. In this proposal we will systematically interrogate the chemistry of astato-substituted boron-heterocycles to develop new methods for 211At-radioastatination and translate basic science discoveries to application ready technology by demonstrating “proof of concept” with a biologically stable small molecule 211At-alpha-RPT.