Prostate cancer is one of the most prevalent malignancies in men and remains a leading cause of cancer-related morbidity and mortality worldwide. For many, prostate cancer follows an indolent course, while others demonstrate aggressive biologic behavior. This highlights the importance of early detection, accurate staging, and biologically informed treatment selection. Nuclear medicine plays a central role in the contemporary management of prostate cancer, providing molecular insights that extend beyond anatomy to interrogate tumor metabolism, proliferation, hypoxia, stromal interactions, and receptor expression. These biologic dimensions are the foundation of both diagnostic imaging and targeted radionuclide therapy. This article provides a biologically structured overview of contemporary non-prostate-specific membrane antigen (PSMA) radiopharmaceuticals used in prostate cancer imaging and therapy, emphasizing the molecular and cellular mechanisms that determine their suitability for diagnostic, therapeutic, or theranostic application. Key determinants of radioligand performance are explored, including physical radionuclide properties, radiochemical stability, molecular internalization and retention, and pharmacologic biodistribution. These factors explain why imaging and therapeutic ligands, although conceptually linked, are not interchangeable and must be carefully matched to biologic behavior and clinical intent. Major biologic imaging pathways relevant to prostate cancer, including glycolytic metabolism, hypoxia, lipid and phospholipid synthesis, amino acid transport and protein synthesis, nucleoside metabolism, androgen receptor signaling, fibroblast activation protein targeting, and skeletal metastasis imaging are reviewed. For each pathway, the molecular rationale for tracer uptake, strengths, and limitations in prostate cancer phenotypes and implications for prognosis and therapy selection are outlined. Importantly, prostate cancer is not a single-pathway disease. Tumor heterogeneity, metabolic plasticity, and microenvironmental adaptation, particularly in castration-resistant disease, necessitate a broader molecular imaging perspective beyond PSMA alone. Although PSMA-targeted imaging and therapy have become clinical mainstays, non-PSMA radioligands retain critical complementary roles in selected clinical scenarios, translational research, and therapy development. This article provides a biologically grounded framework for understanding contemporary prostate cancer radioligands and establishes the foundation for part 2 of this series, which will focus on PSMA-based and emerging molecular strategies shaping the future of prostate cancer theranostics.
Currie et al. (Mon,) studied this question.