Lead radionuclides for theranostic applications in nuclear medicine: from atom to bedside

Lead-212 has emerged as a promising radionuclide for targeted alpha therapy (TAT), positioning itself at the forefront of next-generation cancer treatments. What sets lead-212 apart is its unique decay profile: while it is a beta emitter, it mainly serves as an <i>in vivo</i> generator of the potent alpha-emitting daughter radionuclide bismuth-212. This characteristic offers a versatile radiobiological profile, potentially optimizing therapeutic efficacy by combining the radiochemical characteristics of lead-212 such as easy radiolabeling and practical half-life, with the therapeutic benefit of alpha particles. The relatively short half-life of lead-212 (10.6 hours) offers favorable dosimetric properties, enabling effective treatment while minimizing long-term radiation exposure. Its gamma-emitting analogue, lead-203, is well-suited for single-photon emission computed tomography (SPECT) imaging, forming an ideal theranostic matched pair that can significantly accelerate preclinical and clinical research. Crucially, the generator-based production of lead-212 enables decentralized and on-demand availability, but its half-life also allows centralized production, facilitating broad clinical access and logistical flexibility. In this review, the advantages and challenges of lead-based radiopharmaceuticals are discussed, covering the entire chain from radionuclide production to bedside administration. Special attention is given to the coordination chemistry of lead, and we give an overview of available bifunctional chelators. We also present the latest advancements in preclinical and clinical applications and conclude with perspectives on future directions of lead-based theranostics.