医用同位素^(177)Lu的辐照生产、分离纯化、螯合标记及临床应用

Lutetium-177 radioisotope and therapeutic radiopharmaceuticals:Production,separation and purification,chelation labeling and clinical application

镥是镧系中最后一个元素.在其众多同位素中,^(177)Lu具备诊疗一体化的能力和独特的放射化学性质,在核医学领域发挥着重要的作用.^(177)Lu虽进入核医学治疗领域较晚,但有望成为应用最广泛的治疗放射性核素之一.本文综述了^(177)Lu从发现到规模生产的过程,对“直接法”“间接法”两种主要反应堆生产途径进行了细致的比较,阐明了各自的优势和劣势.从Yb/Lu元素化学性质出发,详细分析阐释了不同分离工艺的设计原理,优缺点及其应用前景.本综述还探讨了^(177)Lu在医学领域中的应用,从以DOTA为标准的重要的螯合剂到核医学螯合剂的探索演变,包括螯合剂设计和对双功能螯合剂深入探讨.另外,本文总结了^(177)Lu放射性药物的应用案例,介绍了以Pluvicto为代表的核药物及其正在进行的临床研究,最后探讨了^(177)Lu的临床应用和未来发展轨迹,并从生产制备、分离纯化、螯合与医学应用的角度对^(177)Lu进行了展望,对我国正在开发的^(177)Lu生产分离工艺和相应核药物的临床研究及其未来应用方向也进行了分析和简要概述.

National health is a critical indicator of a nation’s vitality and economic prosperity.The strategic utilization of medicalisotopes offers a promising approach to enhance individual well-being in the face of challenges posed by various healthconditions.Lutetium(Lu),the last element in the lanthanide series,distinguishes itself through its multiple isotopes,particularly^(177)Lu,which has attracted considerable attention owing to its exceptional nuclear chemistry-related attributesand its dual role in diagnostic imaging and therapeutic interventions.Despite its relatively belated integration into the realmof nuclear medicine therapy compared with other medical isotopes like 131I,^(177)Lu stands poised to ascend as a leadingtherapeutic radionuclide,promising considerable progress in medical treatment paradigms.Beginning in the 1980s and1990s,^(177)Lu gradually moved from experimental to clinical applications,and a series of work on^(177)Lu radiolabeling waspublished.While in 1994,Balasubramanian reported work on the production of carrier-free^(177)Lu by reactor irradiation of anatural Yb target.Ando published work in 1998 on the development of^(177)Lu-EDTMP for the relief of metastatic bonepain.After decades of research and development,^(177)Lu-DOTATATE became the first^(177)Lu radiopharmaceuticals to beapproved for marketing.At the same time,another radiopharmaceutical for the treatment of prostate cancer:^(177)Lu-PSMA617,which has a PSMA target for the treatment of mCRPC,was developed and underwent lots of clinical studies.Thus,^(177)Lu is known as the“gold mine”of radiopharmaceutical development,and research on its unlimited potential has justbegun.This review comprehensively explores the evolution of^(177)Lu,covering its serendipitous discovery and scalableproduction methods as well as the nuanced intricacies underpinning its various production pathways.Moreover,the reviewoffers an in-depth analysis of its primary reactor production routes,i.e.,direct route and indirect route,highlights theadvantages and disadvantages of these routes,and explains theoretical concepts for“radioisotope reactors”.Moreover,thereview comprehensively examines the critical separation and purification stages of the production process of^(177)Lu.It alsopresents a thorough discussion on an exhaustive analysis and exposition of the design principles,benefits,and limitationsof separation techniques,such as ion-exchange chromatography,solvent extraction,and extraction chromatography,basedon 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 themultifaceted therapeutic potential of^(177)Lu 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 incomplexation thermodynamics and radiolabeling kinetics of Lu among different nuclear medicine chelators,with adedicated focus on the strategic design of an optimal chelator with remarkable coordination chemistry ability based onfundamental principles.Moreover,the review presents a comprehensive investigation of bifunctional chelating agents.Thereview also synthesizes case studies on^(177)Lu radiopharmaceuticals,outlining the development of^(177)Lu-DOTATATE,^(177)Lu-EDTMP,and^(177)Lu-PSMA-617,and highlights clinical trials worldwide,with a focus on^(177)Lu-PSMA-617 serving asa prime exemplar.Concluding with an analytical outlook on the clinical deployment and prospective trajectories of^(177)Lu,this review offers a forward-looking analysis of^(177)Lu development,traversing production readiness,separationpurification,chelation strategies,and medical applications.Moreover,it elaborates on^(177)Lu-based pharmaceuticalscurrently under development in China,providing a comprehensive roadmap for the future integration of^(177)Lu in clinicalpractice and medical research endeavors.