Introduction: Poly(adenosine diphoshate ribose) polyermase (PARP) inhibitors are emerging therapeutics that are effective in a small subset of cancers with DNA repair deficiencies. Our goal was to enhance the cellular lethality of PARP inhibitors by introducing an alpha-emitting radiohalogen, astatine-211. The astatination of small molecules has been primarily performed using electrophilic aromatic substitution of tin precursors, which possess an unwanted toxicity profile. Herein we report the direct astatination of small molecule PARP inhibitors using a boronic pinacol ester precursor. Methods: Astatine-211 was produced on a japan steel works BC3015 cyclotron through the Bi-209(alpha,2n)At-211 nuclear reaction and was isolated by dry distillation. PARP inhibitor precursors were prepared using various methods for substituting aryl boronic pinacol esters. Astatination of PARP inhibitors was performed using a copper catalyst system. Final purification of astatine-211 radiolabeled PARP inhibitors was performed using high performance liquid chromatography. Results: Astatine-211 was produced at 11 MBq/µAHr for the proposed studies with final activities after dry distillation ranging from 37 – 74 MBq. Astatination of PARP inhibitors using the copper catalyst system resulted in greater than 95% radionuclide incorporation yields. Final products had high radiochemical and chemical purity. Conclusions: We have demonstrated an alternative approach for the direct astatination of small molecules using boronic esters, which are less toxic than conventional tin precursors. The use of boronic ester precursors has the potential to streamline the clinical translation of astatine-211 radiotherapeutics by avoiding harmful precursor materials, which require extensive testing by regulatory authorities.

Direct astatination of poly(adenosine diphosphate ribose) polymerase inhibitors using boronic acid precursors

255th National Meeting (2018)

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