ACP3-targeted PET imaging agents based on small-molecule ligands for prostate cancer diagnostics and theranostics.

Prostate cancer (PCa) remains a leading cause of cancer-related morbidity and mortality worldwide, underscoring the need for improved molecular imaging strategies. Although prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has changed prostate cancer imaging and treatment, its clinical utility is limited in some settings by heterogeneous tumor expression and substantial off-target uptake in organs such as the kidneys and salivary glands. Acid phosphatase 3 (ACP3), also known as prostatic acid phosphatase, has regained attention as an alternative prostate-associated target because of its abundant expression in prostate cancer and comparatively low expression in several normal tissues. Recent advances in high-affinity small-molecule ligands, including radiolabeled OncoACP3 derivatives, have enabled the development of ACP3-targeted PET radiopharmaceuticals. Preclinical studies and early clinical investigations demonstrate favorable biodistribution, high tumor-to-background contrast, and the capacity to detect lesions in PSMA-low or PSMA-negative disease. Moreover, ACP3-directed radioligand strategies highlight its potential in theranostic applications. Overall, ACP3 radiopharmaceuticals may provide a complementary approach for precision prostate cancer imaging and therapy.