Lutetium-177 radioisotope and therapeutic radiopharmaceuticals:Production,separation and purification,chelation labeling and clinical application
National health is a critical indicator of a nation's vitality and economic prosperity.The strategic utilization of medical isotopes offers a promising approach to enhance individual well-being in the face of challenges posed by various health conditions.Lutetium(Lu),the last element in the lanthanide series,distinguishes itself through its multiple isotopes,particularly 177Lu,which has attracted considerable attention owing to its exceptional nuclear chemistry-related attributes and its dual role in diagnostic imaging and therapeutic interventions.Despite its relatively belated integration into the realm of nuclear medicine therapy compared with other medical isotopes like 131I,177Lu stands poised to ascend as a leading therapeutic radionuclide,promising considerable progress in medical treatment paradigms.Beginning in the 1980s and 1990s,Lu gradually moved from experimental to clinical applications,and a series of work on Lu radiolabeling was published.While in 1994,Balasubramanian reported work on the production of carrier-free 177Lu by reactor irradiation of a natural Yb target.Ando published work in 1998 on the development of 177Lu-EDTMP for the relief of metastatic bone pain.After decades of research and development,177Lu-DOTATATE became the first 177Lu radiopharmaceuticals to be approved for marketing.At the same time,another radiopharmaceutical for the treatment of prostate cancer:Lu-PSMA-617,which has a PSMA target for the treatment of mCRPC,was developed and underwent lots of clinical studies.Thus,177Lu is known as the"gold mine"of radiopharmaceutical development,and research on its unlimited potential has just begun.This review comprehensively explores the evolution of 177Lu,covering its serendipitous discovery and scalable production methods as well as the nuanced intricacies underpinning its various production pathways.Moreover,the review offers an in-depth analysis of its primary reactor production routes,i.e.,direct route and indirect route,highlights the advantages and disadvantages of these routes,and explains theoretical concepts for"radioisotope reactors".Moreover,the review comprehensively examines the critical separation and purification stages of the production process of 177Lu.It also presents a thorough discussion on an exhaustive analysis and exposition of the design principles,benefits,and limitations of separation techniques,such as ion-exchange chromatography,solvent extraction,and extraction chromatography,based on the physical and chemical intricacies of Yb/Lu elements like oxidation states(especially their electrode potential),solubility as well as coordination chemistry.Besides discussing production intricacies,this review assesses the multifaceted therapeutic potential of 177Lu in the medical domain,starting with an examination of DOTA,revered as the"gold standard",and other key chelators such as DTPA and NOTA.Furthermore,the review discusses variations in complexation thermodynamics and radiolabeling kinetics of Lu among different nuclear medicine chelators,with a dedicated focus on the strategic design of an optimal chelator with remarkable coordination chemistry ability based on fundamental principles.Moreover,the review presents a comprehensive investigation of bifunctional chelating agents.The review also synthesizes case studies on 177Lu radiopharmaceuticals,outlining the development of 177Lu-DOTATATE,177Lu-EDTMP,andsiz177CoLu-PSMA-617,and high1ights c1inica1 tria1s wor1dwide,with a focus onme77peLu-PSMA-617 serving as a prime exemplar.Concluding with an analytical outlook on the clinical deployment and prospective trajectories of 177Lu,this review offers a forward-looking analysis of 177Lu development,traversing production readiness,separation purification,chelation strategies,and medical applications.Moreover,it elaborates on 177Lu-based pharmaceuticals currently under development in China,providing a comprehensive roadmap for the future integration of 177Lu in clinical practice and medical research endeavors.
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