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

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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.