Konstantin Egon Seifert,Julissa Reimann,Martin Rust,Martin Bögemann,Andres Jan Schrader,Michael Schäfers,Christof Bernemann,Philipp Backhaus

Seminars in Nuclear Medicine

DOI: 10.1053/j.semnuclmed.2026.03.004

Abstract

Prostate-specific membrane antigen (PSMA)-targeted theranostics have transformed the diagnostic and therapeutic landscape of prostate cancer; however, clinically relevant limitations persist, including heterogeneous or absent PSMA expression in a substantial subset of tumors and dose-limiting off-target uptake in salivary glands, lacrimal glands and kidneys. Prostatic acid phosphatase (ACP3), expressed in more than 95% of prostate cancers, has re-emerged as a promising complementary and potentially alternative theranostic target. ACP3 demonstrates favorable biological characteristics, including high and consistent tumor expression, persistence in castration-resistant disease, and minimal expression in critical but non-cancerous tissues. Recent advances in ligand discovery using DNA-encoded chemical libraries have enabled the development of high-affinity ACP3-targeting compounds, with successful first-in-human molecular imaging with [68Ga]Ga-OncoACP3-DOTA PET. Early clinical data demonstrate competitive diagnostic performance compared with PSMA-PET, markedly reduced salivary/lacrimal gland and renal uptake, and advantageous pharmacokinetics characterized by increasing tumor uptake and improving tumor-to-background ratios over time. Preclinical and translational evidence further supports the feasibility of ACP3-targeted radioligand therapy. This review summarizes the biological features of ACP3, its historical and current role as a biomarker, and emerging therapeutic applications, with a primary focus on ACP3-targeted molecular imaging and radioligand therapy. The available evidence positions ACP3 as a compelling next-generation theranostic target with the potential to overcome key limitations of PSMA-based approaches and expand precision treatment options for patients with prostate cancer.