[177Lu]Lu-PSMA-617

[177Lu]Lu-PSMA-617 (lutetium-177 PSMA-617, also known by the brand name Pluvicto) is a targeted radioligand therapy (RLT) consisting of a small-molecule inhibitor of prostate-specific membrane antigen (PSMA) — the protein product of the gene encoding Glutamate carboxypeptidase II (GCPII) — conjugated to the macrocyclic chelator DOTA and radiolabeled with the beta-emitting radionuclide lutetium-177 (¹⁷⁷Lu). PSMA is a type II transmembrane protein that is overexpressed on the surface of prostate cancer cells, as well as on the neovasculature of a range of solid tumors, making it an attractive theranostic target. Upon systemic administration, [177Lu]Lu-PSMA-617 binds with high affinity to PSMA-expressing tumor cells, delivering localized ionizing radiation that induces DNA double-strand breaks and consequent cell death, while sparing surrounding normal tissue to a comparatively greater extent than conventional chemotherapy.

The agent exemplifies the theranostic paradigm: a structurally analogous gallium-68-labeled compound ([68Ga]Ga-PSMA-11 or related analogs) enables PSMA positron emission tomography (PET) imaging to identify patients whose tumors express sufficient PSMA for therapeutic targeting, predict dosimetry, and monitor treatment response. [177Lu]Lu-PSMA-617 received regulatory approval by the U.S. Food and Drug Administration in 2022 for adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been previously treated with Androgen receptor (AR) pathway inhibitors and taxane-based chemotherapy, marking a paradigm shift in the management of advanced prostate cancer.