Synthesis and preliminary evaluation of 211At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer

Introduction: The high potency and short tissue range of a-particles are attractive features for targeted radionuclide therapy, particularly for cancerswithmicro-metastases. In the current study, we describe the synthesis of a series of At-211-labeled prostate-specificmembrane antigen (PSMA) inhibitors and their preliminary evaluation as potential agents for metastatic prostate cancer treatment. Methods: Four novel Glu-urea based PSMA ligands containing a trialkyl stannyl group were synthesized and labeled with At-211, and for comparative purposes, I-131, via halodestannylation reactions with N-chlorosuccinimide as the oxidant. A PSMA inhibitory assay was performed to evaluate PSMA binding of the unlabeled, iodinated compounds. A series of paired-label biodistribution experiments were performed to compare each At-211-labeled PSMA ligand to its I-131-labeled counterpart in mice bearing subcutaneous PC3 PSMA+ PIP xenografts. Results: Radiochemical yields ranged from 32% to 65% for the At-211-labeled PSMA inhibitors and were consistently lower than those obtained with the corresponding I-131-labeled analogue. Good localization in PC3 PSMA+ PIP but not control xenografts was observed for all labeled molecules studied, which exhibited a variable degree of in vivo dehalogenation as reflected by thyroid and stomach activity levels. Normal tissue uptake and in vivo stability for several of the compounds wasmarkedly improved comparedwith the previously evaluated compounds, [At-211]DCABzL and [*I]DCIBzL. Conclusions and implications for patient care: Compared with the first generation compound [At-211]DCABzL, several of the novel At-211-labeled PSMAligands exhibitedmarkedly improved stability in vivo and higher tumor-to-normal tissue ratios. [At-211]GV-620 has the most promising characteristics and warrants further evaluation as a targeted radiotherapeutic for prostate cancer. (C) 2021 Elsevier Inc. All rights reserved.