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 α-particles are attractive features for targeted radionuclide therapy, particularly for cancers with micro-metastases. In the current study, we describe the synthesis of a series of ²¹¹At-labeled prostate-specific membrane 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 ²¹¹At, and for comparative purposes, ¹³¹I, 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 ²¹¹At-labeled PSMA ligand to its ¹³¹I-labeled counterpart in mice bearing subcutaneous PC3 PSMA+ PIP xenografts. Results: Radiochemical yields ranged from 32% to 65% for the ²¹¹At-labeled PSMA inhibitors and were consistently lower than those obtained with the corresponding ¹³¹I-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 was markedly improved compared with the previously evaluated compounds, [²¹¹At]DCABzL and [*I]DCIBzL. Conclusions and implications for patient care: Compared with the first generation compound [²¹¹At]DCABzL, several of the novel ²¹¹At-labeled PSMA ligands exhibited markedly improved stability in vivo and higher tumor-to-normal tissue ratios. [²¹¹At]GV-620 has the most promising characteristics and warrants further evaluation as a targeted radiotherapeutic for prostate cancer.