Copper-mediated astatination of 211At-labelled prostate-specific membrane antigen probes in the presence of basic salts

Abstract

Highly toxic alpha emitting radionuclide, astatine-211 (211At) labelled compounds have great potential as therapeutic radiopharmaceuticals in the targeted alpha therapy (TAT). Previously we have reported the usefulness of copper (Cu)-mediated radiobromination and radioiodination via boronic acid precursors for the synthesis of 77Br/125I-labelled prostate-specific membrane antigen (PSMA) inhibitors which are applicable as imaging probes. This background led us to investigate the Cu-mediated astatination of PSMA inhibitors as a therapeutic agent for TAT. 211At-labelled PSMA inhibitors [211At]mAtB-PS were synthesised from a boronic acid precursor with tert-butoxycarbonyl groups by Cu-mediated astatination in the presence or absence of NaOH and K2CO3 in order to stabilize the chemical form of At followed by deprotection of the tert-butoxycarbonyl group under acidic condition. We confirmed that [211At]mAtB-PS 1a was synthesised in 64.4–87.3% of overall radiochemical yields (RCYs). These yields are considered acceptable regardless of basic salts existed. However, RCYs of the astatination step differed depending on the base (NaOH: 22.0–31.9%; K2CO3; 69.0–82.3%; without base: 60.1%). We speculated that astatination also occurred during the deprotection of tert-butoxycarbonyl groups. This could be attributed to an electrophilic deboronation reaction involving electrophilic astatine species, resulting in compensation for the overall RCYs. Cu-mediated astatination via boronic precursors was found to be very effective for the synthesis of 211At-labelled PSMA inhibitors for the targeted alpha therapy.