Radiotheranostics Using a Novel 225Ac-Labeled Radioligand with Improved Pharmacokinetics Targeting Prostate-Specific Membrane Antigen.

Abstract

225Ac-based radiotheranostics targeting prostate-specific membrane antigen (PSMA) has induced impressive responses in patients with metastatic castration-resistant prostate cancer. To enhance the therapeutic effects of radioligands labeled with 225Ac (half-life: 10 days), a radioligand that shows longer tumor retention would be useful. Here, we designed and synthesized a straight-chain PSMA-targeting radioligand, PSMA-DA1, which includes an (iodophenyl)butyric acid derivative as an albumin binder (ALB). We performed preclinical evaluations of PSMA-DA1 as a tool for PSMA-targeting radiotheranostics using 111In, 90Y, and 225Ac. [111In]In-PSMA-DA1 demonstrated significantly greater tumor uptake and retention than a corresponding non-ALB-conjugated compound. In mice, single-photon emission computed tomography performed with [111In]In-PSMA-DA1 produced clear tumor images, and the administration of [90Y]Y-PSMA-DA1 or [225Ac]Ac-PSMA-DA1 inhibited tumor growth. [225Ac]Ac-PSMA-DA1 had antitumor effects in mice at a lower radioactivity level than [225Ac]Ac-PSMA-617, which has been reported to be clinically useful. These results indicate that PSMA-DA1 may be a useful PSMA-targeting radiotheranostic agent.

• Authors: Shimpei Iikuni, Yuta Tarumizu, Kazuma Nakashima, Yusuke Higaki, Hiroaki Ichikawa, Hiroyuki Watanabe, Masahiro Ono
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 18 Pg. 13429-13438 (09 23 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34477385 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actinium-225
• Antineoplastic Agents
• Cyclams
• Ligands
• Membrane Glycoproteins
• Radiopharmaceuticals
• Urea
• Glutamate Carboxypeptidase II
• PSMA protein, mouse
• Actinium

Topics

• Actinium (chemistry)
• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Cyclams (chemical synthesis, metabolism, pharmacokinetics, therapeutic use)
• Glutamate Carboxypeptidase II (metabolism)
• Humans
• Ligands
• Male
• Membrane Glycoproteins (metabolism)
• Mice, Inbred ICR
• Mice, SCID
• Precision Medicine (methods)
• Prostatic Neoplasms, Castration-Resistant (diagnostic imaging, drug therapy, metabolism)
• Radiopharmaceuticals (chemical synthesis, metabolism, pharmacokinetics, therapeutic use)
• Single Photon Emission Computed Tomography Computed Tomography
• Urea (analogs & derivatives, metabolism, pharmacokinetics, therapeutic use)
• Xenograft Model Antitumor Assays
• Mice