Two Targets, One Mission: Heterobivalent Metal‐Based Radiopharmaceuticals for Prostate Cancer Imaging and Therapy

Prostate cancer (PCa) is a significant healthcare challenge, associated with considerable mortality and morbidity among men, particularly in developed countries. PCa mortality and morbidity are primarily related to its most advanced form, metastatic castration-resistant PCa (mCRPC), for which there is presently no cure. Therefore, novel therapeutic approaches to increase mCRPC survival are critically needed. Due to PCa tumor heterogeneity and a complex tumor microenvironment, the efficacy of single-target radiopharmaceuticals, such as the Food and Drug Administration-approved [¹⁷⁷Lu]Lu-PSMA-617, is currently under reassessment. The design and development of PCa dual-target radiopharmaceuticals have garnered considerable attention, due to their benefits over single-target counterparts, namely increased therapeutic specificity and efficacy, as well as the ability to overcome the challenge of inconsistent tumor visualization caused by variable receptor expression across diverse lesions, thereby enabling more comprehensive imaging. Several PCa biomarkers are currently being investigated as potential targets for dual-target radiopharmaceuticals, including prostate-specific membrane antigen, gastrin-releasing peptide receptor, integrin α_vβ₃ receptor, fibroblast activation protein, sigma-1 receptor, as well as albumin, the radiosensitive cell nucleus, and mitochondria. This review explores recent advancements in heterobivalent metal-based radiopharmaceuticals for dual targeting in PCa, highlighting their significance in theranostic and personalized medicine.