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

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $325,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10430255
- **Project number:** 5R21EB032027-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Hsiaoju Sharon Lee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $325,000
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430255

## Citation

> US National Institutes of Health, RePORTER application 10430255, Novel chemistry to improve the biostability of organo-astatine bonds in alpha-emitting radiopharmaceutical therapeutics (5R21EB032027-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10430255. Licensed CC0.

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