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

摘要/概要 在现有的少数几种能发射γ射线的放射性核素中，211 At是最有前途的放射性核素之一。 放射性核素，因为它的物理和化学性质是完美的匹配， 放射性药物治疗剂（RPTs）用于治疗其他不可治愈的肿瘤。但是经 211 At从药理学靶向构建体的体内释放降低了治疗功效， 对正常组织的毒性，并且是实现211 At-100-RPT的真正潜力的最大障碍。这 该提案直接解决了开发用于改善有机-<$素的新型化学品的关键未满足需求 结合稳定性，以防止其在体内释放。碳-卤键强度与卤素成负相关 尺寸最大，作为最大的卤素，碳-At（C-At）的键强度最弱，这使得它 更容易在体内氧化脱卤。目前，大多数211 At-缀合方法使用C-At键 因此生物稳定性差。可替代地，使用硼-<$（B-At）键，其比 C-At键是提高~（211）At-β-RPT体内稳定性的有效策略。因此，我们建议 研究以前未开发的硼杂原子环系统，这些系统非常适合作为药物 开发生物稳定的211 At-100-RPT。这些环系统建立了卤化化学 适合于在环系统中的硼或碳位置上进行astatine取代，每一个都提供独特的 具有增强稳定性的性质，并能够实现211 At-放射性的正交路线。在本提案中，我们 将系统地研究阿托取代的硼杂环的化学，以开发新的方法 为211 At-放射性同位素，并将基础科学发现转化为应用准备技术， 证明了用生物稳定的小分子211 At-211-RPT的“概念验证”。

Abstract/Summary Of the few -emitting radionuclides that exist, astatine-211 (211At) is one of the most promising -emitting radionuclides, because its physical and chemical properties are perfectly matched for -emitting radiopharmaceutical therapeutics (-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--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--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--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--RPT.