Effect of Carbon-Chain Length in [125i]iodophenyl and [211at]astatophenyl Derivatives on Prostate-Specific Membrane Antigen-Targeted Radioligands.

Prostate cancer remains a leading cause of cancer-related mortality. Targeted alpha therapy using 211At is a promising treatment, although the low tumor-to-kidney ratios of 211At-labeled agents pose a persistent challenge. In this study, we designed prostate-specific membrane antigen (PSMA)-targeted radioligands incorporating 125I-labeled p-iodophenyl (IP) or 211At-labeled p-astatophenyl (AP) derivatives with different carbon-chain lengths and evaluated their impact on pharmacokinetics. In biodistribution studies, while [125I]IP-Cn-PSMA (n = 1, 2, or 4) exhibited low blood retention or high renal uptake, [125I]IP-C3-PSMA showed marked blood retention and low renal uptake, resulting in a higher tumor-to-kidney ratio compared with [125I]IP-C1-PSMA. [211At]AP-C1-PSMA and [211At]AP-C3-PSMA showed pharmacokinetic trends in the blood and kidneys comparable to those of the corresponding 125I-labeled compounds, despite partial deastatination. These results suggest that C3-chain-based IP and AP derivatives are effective for improving the tumor-to-kidney ratio, although the C1-chain-based derivatives retain advantages in early pharmacokinetics. Further comprehensive evaluations in tumor-bearing mice are required to determine the optimal candidate for PSMA-targeted 211At-labeled agents, potentially involving additional pharmacokinetic fine-tuning.