²²⁵Ac‑RAX104: A Next‑Generation PSMA Alpha Radioligand for Advanced Prostate Cancer

RAX104 is a small molecule ligand designed specifically to target PSMA, the protein that is highly expressed on the surface of prostate cancer cells. When labeled with ²²⁵Ac, it forms a radioligand that combines the physical advantages of actinium‑225 (high linear energy transfer and a 10‑day half‑life) with a ligand engineered for better tumor retention. The molecule was successfully synthesized and labeled with ²²⁵Ac, achieving radiochemical purity above 95% and remaining stable for more than 110 hours, which is important for practical use in preclinical and clinical settings.

In biochemical tests, the RAX104 precursor showed roughly 22‑fold higher affinity for PSMA than the classic PSMA‑617 ligand(the one used by Pluvicto), mainly because it dissociates more slowly from the receptor. This means it sticks to the tumor cells longer rather than washing away quickly from the bloodstream. In PSMA‑overexpressing PC3 prostate cancer cells, ²²⁵Ac‑RAX104 also showed markedly higher cellular uptake and internalization compared with ²²⁵Ac‑PSMA‑617, confirming that the improved binding translates into better delivery of radiation inside the cells.

When tested in PSMA‑low 22Rv1 xenograft models, ²²⁵Ac‑RAX104 delivered more than three times higher absorbed activity in tumors than ²²⁵Ac‑PSMA‑617 over time, while both radioligands had similar behavior in the blood. This indicates that the new ligand concentrates more radiation inside the tumor without significantly increasing systemic exposure, which is exactly what you want to maximize efficacy while keeping toxicity in check. The longer biological half‑life of ²²⁵Ac‑RAX104 in tumors also means that the α‑particles are released over a longer period right where they are needed, aligning well with the 9.92‑day physical half‑life of ²²⁵Ac.

In terms of antitumor effect, a single 14.8 kBq dose of ²²⁵Ac‑RAX104 produced stronger tumor‑growth inhibition and longer survival in the 22Rv1 model than  a fivefold higher dose of ²²⁵Ac‑PSMA‑617. This suggests that ²²⁵Ac‑RAX104 can achieve better therapeutic outcomes at much lower radiation activities, potentially reducing the risk of side effects while still controlling the disease more effectively. In normal ICR mice, the compound caused only transient and reversible reductions in white blood cell, neutrophil, and reticulocyte counts, without major abnormalities in blood chemistry, pointing to a relatively favorable safety profile at these doses.

This has led to the proposal of an investigator‑initiated trial in men with mCRPC, aimed at generating human dosimetry and safety data to guide future clinical development.

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