Production and chelation chemistry of radiolanthanides

放射性镧系元​​素的生产和螯合化学

• 批准号: RGPIN-2022-03887
• 负责人: Yang, Hua
• 金额: $ 1.82万
• 依托单位: TRIUMF
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761537
• 关键词: Production; chelation; chemistry; radiolanthanides

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.

近年来，使用新一代放射性同位素如177 Lu、225 Ac、223 Ra的靶向放射性核素治疗（TRT）由于对晚期癌症的治疗效果而引起了全球的关注。TRT包含粒子发射同位素、可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调查放射性镧系元素和它们的螯合化学TRT。 放射性镧系元素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，但除了商业上可获得的177 Lu，它们的生产和放射化学在很大程度上还未被探索。在我的新兴研究计划中，我们的目标是通过研究它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132/135 La，141 Ce，149/152/155/161 Tb和165 Er。132/135 La可以作为225 Ac药物的成像伙伴。141 Ce可以作为痕量金属来测试分离化学和放射性标记。149 Tb（α-发射体）、152 Tb（PET同位素）、155 Tb（SPECT同位素）沿着反应器产生的161 Tb（β-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。165 Er是一种纯俄歇电子发射体。沿着161 Tb（AE和β-发射体）、177 Lu（纯β-发射体）和149 Tb（α-发射体），它将使得能够使用相同的生物缀合物研究不同颗粒的放射生物学效应。拟议的同位素沿着177 Lu也将允许测试镧系元素之间微妙和独特的螯合化学。 虽然镧系元素配合物的光学和磁性已被广泛研究，但用于177 Lu以外的放射性镧系元素的螯合物仅限于少数实例。许多工作要做，以开发新的螯合物与放射性镧系元素和了解他们的配位化学。我们计划使用固相合成来产生螯合剂池，并测试高通量标记方法。我们还将利用Tb配合物的发光特性，并制备具有152/155 Tb的双峰成像探针（光学和PET/SPECT）。 该计划将通过研究非常规同位素和新型螯合剂的合成和标记方法，极大地扩展我们在放射性镧系元素和螯合剂方面的知识和经验。它将为核医学和放射性药物开发提供新的工具，并通过提供这些稀有医用同位素和螯合剂使加拿大研究界受益。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癌症的长期合作。