Effect of Carbon-Chain Length in [¹²⁵I]iodophenyl and [²¹¹At]astatophenyl Derivatives on Prostate-Specific…

Abstract

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.

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BibTeX RIS

BibTeX

@article{nakashima2026effect,
  title = {{Effect of Carbon-Chain Length in [¹²⁵I]iodophenyl and [²¹¹At]astatophenyl Derivatives on Prostate-Specific Membrane Antigen-Targeted Radioligands}},
  author = {Kazuma Nakashima and Honoka Asahina and Takuma Hasegawa and Hiroyuki Fujimoto and Masashi Murakami and Kazuhiro Ooe and Atsushi Toyoshima and Hiroyuki Watanabe and Masahiro Ono},
  journal = {Chemical and Pharmaceutical Bulletin},
  year = {2026},
  month = sep,
  doi = {10.1248/cpb.c26-00140},
  url = {https://www.jstage.jst.go.jp/article/cpb/74/9/74_c26-00140/_article},
  note = {CC BY-NC},
}

RIS

TY  - JOUR
TI  - Effect of Carbon-Chain Length in [¹²⁵I]iodophenyl and [²¹¹At]astatophenyl Derivatives on Prostate-Specific Membrane Antigen-Targeted Radioligands
AU  - Kazuma Nakashima
AU  - Honoka Asahina
AU  - Takuma Hasegawa
AU  - Hiroyuki Fujimoto
AU  - Masashi Murakami
AU  - Kazuhiro Ooe
AU  - Atsushi Toyoshima
AU  - Hiroyuki Watanabe
AU  - Masahiro Ono
PY  - 2026
DA  - 2026/09/01
JO  - Chemical and Pharmaceutical Bulletin
DO  - 10.1248/cpb.c26-00140
UR  - https://www.jstage.jst.go.jp/article/cpb/74/9/74_c26-00140/_article
AB  - 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.
SN  - 1347-5223
SN  - 0009-2363
ER  -

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