[225Ac]Ac-PSMA-R2: An Investigational Radioligand Therapy for Prostate Cancer

1. Introduction to [225Ac]Ac-PSMA-R2

[[225Ac]Ac-PSMA-R2 is an investigational radioligand therapy (RLT) representing a novel approach in the management of prostate cancer.1 This therapeutic agent is a conjugate composed of two principal components: PSMA-R2, a ligand specifically designed to target the Prostate-Specific Membrane Antigen (PSMA), and Actinium-225 ($^{225}$Ac), a potent alpha-emitting radionuclide.1 PSMA is a transmembrane protein that is significantly overexpressed on the surface of prostate cancer cells, and its expression levels often correlate with tumor aggressiveness and metastatic potential, making it an attractive molecular target for directed therapies.3 Actinium-225 is chosen for its high linear energy transfer (LET) and short particle range, characteristics that theoretically confer a high degree of cytotoxicity to targeted cells with limited damage to surrounding healthy tissue.3]

[The therapeutic rationale for [225Ac]Ac-PSMA-R2 centers on the precise delivery of highly damaging alpha radiation directly to PSMA-expressing prostate cancer cells, including those forming metastatic lesions.1 This targeted approach aims to maximize tumor cell kill while minimizing systemic toxicity. The agent is currently under investigation for patients with both metastatic castration-resistant prostate cancer (mCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC).1 The mCRPC setting, particularly in heavily pre-treated patients, presents a significant clinical challenge due to the common development of resistance to standard therapies and limited subsequent treatment options.2 Targeted alpha therapies such as [225Ac]Ac-PSMA-R2 offer a promising strategy to potentially overcome these resistance mechanisms.3]