Production and chelation chemistry of radiolanthanides

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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.