Production and chelation chemistry of radiolanthanides

近年来，使用新一代放射性同位素如177Lu、225Ac、223Ra的靶向放射性核素治疗(TRT)引起了全球的关注，因为它对晚期癌症的治疗效果有限。TRT包括粒子发射同位素、能够稳定携带放射性有效载荷的螯合剂和靶向载体。我的研究计划的目标是研究放射性镧系元素及其在TRT中的螯合化学。放射性稀土是一大类放射性同位素，为所有主要的核医学模式提供选择，包括SPECT、PET成像以及α-、β-和俄歇治疗。尽管有潜力，但除了商业上可用的177Lu之外，它们的生产和放射化学在很大程度上还没有得到充分开发。在我的新兴研究计划中，我们的目标是通过调查他们的生产方法和配位化学来解决这一知识差距。我们将探索的同位素包括132/135La、141Ce、149/152/155/161Tb和165Er。132/135La可以作为225Ac药物的成像伙伴。~(141)Ce可作为痕量金属用于检测分离化学和放射性标记。149Tb(阿尔法发射体)、152Tb(PET同位素)、155Tb(SPECT同位素)，以及反应堆生产的161Tb(贝塔发射体)，允许使用化学上相同的放射性药物进行治疗和成像。165Er是一种纯俄歇电子发射体。与161Tb(声发射和贝塔发射体)、177Lu(纯贝塔发射体)和149Tb(阿尔法发射体)一起，它将能够研究使用相同生物结合物的不同粒子的放射生物学效应。拟议的同位素以及177Lu还将允许测试整个镧系元素系列中微妙而独特的螯合化学。尽管稀土络合物的光学和磁学性质已经得到了广泛的研究，但用于177Lu以外的放射性稀土的络合物仅限于少数几个例子。要与稀土元素形成新的络合物并了解它们的配位化学，还有很多工作要做。我们计划使用固相合成来生成螯合剂池，并测试高通量的标记方法。我们还将挖掘Tb络合物的潜在发光性质，并制备152/155Tb的双模成像探针(光学和PET/SPECT)。该项目将通过研究非常规同位素和新的螯合剂合成和标记方法，极大地扩展我们在放射性稀土和螯合剂方面的知识和经验。它将在核医学和放射性药物开发方面提供新的工具，并通过提供这些稀有的医用同位素和螯合剂使加拿大研究社区受益。该计划还提供了一个跨学科的HQP培训平台，涵盖了广泛的放射化学和化学专业知识，利用我们独特的基础设施、深厚的专业知识以及与SFU、UBC和BC癌症公司的长期合作。

In recent years, targeted radionuclide therapy (TRT) using new generation radioisotopes such as 177Lu, 225Ac, 223Ra has drawn global interest because of demonstrated therapeutic efficacy for late-stage cancers with limited alternatives. TRT comprises a particle emitting isotope, a chelator that can stably carry the radioactive payload, and a targeting vector. The goal for my research program is to investigate radiolanthanides and their chelation chemistry for TRT. Radiolanthanides are a large group of radioisotopes that provide options for all major nuclear medicine modalities, including SPECT, PET imaging, and alpha-, beta- and Auger therapy. Despite the potentials, other than commercially available 177Lu, their production and radiochemistry are largely underexplored. In my emerging research program, we aim to address this knowledge gap by investigating their production methods and coordination chemistry. The isotopes we will explore include 132/135La, 141Ce, 149/152/155/161Tb and 165Er. 132/135La can work as imaging partners for 225Ac drugs. 141Ce can serve as a trace metal to test the separation chemistry and radiolabeling. 149Tb (alpha-emitter), 152Tb (PET isotope), 155Tb (SPECT isotope), along with reactor-produced 161Tb (beta-emitter) allow therapy and imaging with chemically identical radiopharmaceuticals. 165Er is a pure Auger electron emitter. Along with 161Tb (AE and beta-emitter), 177Lu (pure beta-emitter) and 149Tb (alpha-emitter), it will enable studying the radiobiological effect of different particles using the same bioconjugates. The proposed isotopes along with 177Lu will also allow testing of the subtle and distinct chelation chemistry across the lanthanide series. Although lanthanide complexes have been extensively studied for their optical and magnetic properties, chelates used for radiolanthanides other than 177Lu are limited to a handful of examples. Much work is to be done to develop new chelates with radiolanthanides and understand their coordination chemistry. We plan to use solid phase synthesis to generate a chelator pool, and test high throughput  labeling methods.  We will also tap into the  luminescent properties of Tb complexes and prepare dimodality imaging probes (optical and PET/SPECT) with 152/155Tb. This program will greatly expand our knowledge and experience with radiolanthanides and chelators by investigating unconventional isotopes and novel chelator synthesis and labeling methods. It will provide new tools in nuclear medicine and radiopharmaceutical development, and benefit Canadian research communities by giving access to those rare medical isotopes and chelators. This program also provides an interdisciplinary HQP training platform that covers a broad range of radiochemistry and chemistry expertise, leveraging our unique infrastructure, deep expertise and long standing collaborations with SFU, UBC and BC Cancer.