Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals
A comprehensive investigation of the Hg2+ coordination chemistry and 197m/gHg radiolabeling capabilities of cyclen-based commercial chelators, namely, DOTA and DOTAM (aka TCMC), along with their bifunctional counterparts, p-SCN-Bn-DOTA and p-SCN-Bn-TCMC, was conducted to assess the suitability of th...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2024.1292566/full |
| _version_ | 1797320947680673792 |
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| author | Parmissa Randhawa Parmissa Randhawa Imma Carbo-Bague Imma Carbo-Bague Patrick R. W. J. Davey Patrick R. W. J. Davey Shaohuang Chen Shaohuang Chen Helen Merkens Carlos F. Uribe Chengcheng Zhang Marianna Tosato Marianna Tosato François Bénard Valery Radchenko Valery Radchenko Caterina F. Ramogida Caterina F. Ramogida |
| author_facet | Parmissa Randhawa Parmissa Randhawa Imma Carbo-Bague Imma Carbo-Bague Patrick R. W. J. Davey Patrick R. W. J. Davey Shaohuang Chen Shaohuang Chen Helen Merkens Carlos F. Uribe Chengcheng Zhang Marianna Tosato Marianna Tosato François Bénard Valery Radchenko Valery Radchenko Caterina F. Ramogida Caterina F. Ramogida |
| author_sort | Parmissa Randhawa |
| collection | DOAJ |
| description | A comprehensive investigation of the Hg2+ coordination chemistry and 197m/gHg radiolabeling capabilities of cyclen-based commercial chelators, namely, DOTA and DOTAM (aka TCMC), along with their bifunctional counterparts, p-SCN-Bn-DOTA and p-SCN-Bn-TCMC, was conducted to assess the suitability of these frameworks as bifunctional chelators for the 197m/gHg2+ theranostic pair. Radiolabeling studies revealed that TCMC and DOTA exhibited low radiochemical yields (0%–6%), even when subjected to harsh conditions (80°C) and high ligand concentrations (10–4 M). In contrast, p-SCN-Bn-TCMC and p-SCN-Bn-DOTA demonstrated significantly higher 197m/gHg radiochemical yields (100% ± 0.0% and 70.9% ± 1.1%, respectively) under the same conditions. The [197 m/gHg]Hg-p-SCN-Bn-TCMC complex was kinetically inert when challenged against human serum and glutathione. To understand the differences in labeling between the commercial chelators and their bifunctional counterparts, non-radioactive natHg2+ complexes were assessed using NMR spectroscopy and DFT calculations. The NMR spectra of Hg-TCMC and Hg-p-SCN-Bn-TCMC suggested binding of the Hg2+ ion through the cyclen backbone framework. DFT studies indicated that binding of the Hg2+ ion within the backbone forms a thermodynamically stable product. However, competition can form between isothiocyanate binding and binding through the macrocycle, which was experimentally observed. The isothiocyanate bound coordination product was dominant at the radiochemical scale as, in comparison, the macrocycle bound product was seen at the NMR scale, agreeing with the DFT result. Furthermore, a bioconjugate of TCMC (TCMC-PSMA) targeting prostate-specific membrane antigen was synthesized and radiolabeled, resulting in an apparent molar activity of 0.089 MBq/nmol. However, the complex demonstrated significant degradation over 24 h when exposed to human serum and glutathione. Subsequently, cell binding assays were conducted, revealing a Ki value ranging from 19.0 to 19.6 nM. This research provides crucial insight into the effectiveness of current commercial chelators in the context of 197m/gHg2+ radiolabeling. It underscores the necessity for the development of specific and customized chelators to these unique “soft” radiometals to advance 197m/gHg2+ radiopharmaceuticals. |
| first_indexed | 2024-03-08T04:50:27Z |
| format | Article |
| id | doaj.art-2d2c5a23232b4b0aa52bcf207a58b8ad |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-03-08T04:50:27Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-2d2c5a23232b4b0aa52bcf207a58b8ad2024-02-08T05:06:50ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462024-02-011210.3389/fchem.2024.12925661292566Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticalsParmissa Randhawa0Parmissa Randhawa1Imma Carbo-Bague2Imma Carbo-Bague3Patrick R. W. J. Davey4Patrick R. W. J. Davey5Shaohuang Chen6Shaohuang Chen7Helen Merkens8Carlos F. Uribe9Chengcheng Zhang10Marianna Tosato11Marianna Tosato12François Bénard13Valery Radchenko14Valery Radchenko15Caterina F. Ramogida16Caterina F. Ramogida17Department of Chemistry, Simon Fraser University, Burnaby, BC, CanadaLife Sciences Division, TRIUMF, Vancouver, BC, CanadaDepartment of Chemistry, Simon Fraser University, Burnaby, BC, CanadaLife Sciences Division, TRIUMF, Vancouver, BC, CanadaDepartment of Chemistry, Simon Fraser University, Burnaby, BC, CanadaLife Sciences Division, TRIUMF, Vancouver, BC, CanadaDepartment of Chemistry, Simon Fraser University, Burnaby, BC, CanadaLife Sciences Division, TRIUMF, Vancouver, BC, CanadaDepartment of Molecular Oncology, BC Cancer, Vancouver, BC, CanadaDepartment of Molecular Oncology, BC Cancer, Vancouver, BC, CanadaDepartment of Molecular Oncology, BC Cancer, Vancouver, BC, CanadaDepartment of Chemistry, Simon Fraser University, Burnaby, BC, CanadaLife Sciences Division, TRIUMF, Vancouver, BC, CanadaDepartment of Molecular Oncology, BC Cancer, Vancouver, BC, CanadaLife Sciences Division, TRIUMF, Vancouver, BC, CanadaDepartment of Chemistry, University of British Columbia, Vancouver, BC, CanadaDepartment of Chemistry, Simon Fraser University, Burnaby, BC, CanadaLife Sciences Division, TRIUMF, Vancouver, BC, CanadaA comprehensive investigation of the Hg2+ coordination chemistry and 197m/gHg radiolabeling capabilities of cyclen-based commercial chelators, namely, DOTA and DOTAM (aka TCMC), along with their bifunctional counterparts, p-SCN-Bn-DOTA and p-SCN-Bn-TCMC, was conducted to assess the suitability of these frameworks as bifunctional chelators for the 197m/gHg2+ theranostic pair. Radiolabeling studies revealed that TCMC and DOTA exhibited low radiochemical yields (0%–6%), even when subjected to harsh conditions (80°C) and high ligand concentrations (10–4 M). In contrast, p-SCN-Bn-TCMC and p-SCN-Bn-DOTA demonstrated significantly higher 197m/gHg radiochemical yields (100% ± 0.0% and 70.9% ± 1.1%, respectively) under the same conditions. The [197 m/gHg]Hg-p-SCN-Bn-TCMC complex was kinetically inert when challenged against human serum and glutathione. To understand the differences in labeling between the commercial chelators and their bifunctional counterparts, non-radioactive natHg2+ complexes were assessed using NMR spectroscopy and DFT calculations. The NMR spectra of Hg-TCMC and Hg-p-SCN-Bn-TCMC suggested binding of the Hg2+ ion through the cyclen backbone framework. DFT studies indicated that binding of the Hg2+ ion within the backbone forms a thermodynamically stable product. However, competition can form between isothiocyanate binding and binding through the macrocycle, which was experimentally observed. The isothiocyanate bound coordination product was dominant at the radiochemical scale as, in comparison, the macrocycle bound product was seen at the NMR scale, agreeing with the DFT result. Furthermore, a bioconjugate of TCMC (TCMC-PSMA) targeting prostate-specific membrane antigen was synthesized and radiolabeled, resulting in an apparent molar activity of 0.089 MBq/nmol. However, the complex demonstrated significant degradation over 24 h when exposed to human serum and glutathione. Subsequently, cell binding assays were conducted, revealing a Ki value ranging from 19.0 to 19.6 nM. This research provides crucial insight into the effectiveness of current commercial chelators in the context of 197m/gHg2+ radiolabeling. It underscores the necessity for the development of specific and customized chelators to these unique “soft” radiometals to advance 197m/gHg2+ radiopharmaceuticals.https://www.frontiersin.org/articles/10.3389/fchem.2024.1292566/fullradiopharmaceuticalsTCMCmercury-197HgradiometalsDOTAM |
| spellingShingle | Parmissa Randhawa Parmissa Randhawa Imma Carbo-Bague Imma Carbo-Bague Patrick R. W. J. Davey Patrick R. W. J. Davey Shaohuang Chen Shaohuang Chen Helen Merkens Carlos F. Uribe Chengcheng Zhang Marianna Tosato Marianna Tosato François Bénard Valery Radchenko Valery Radchenko Caterina F. Ramogida Caterina F. Ramogida Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals Frontiers in Chemistry radiopharmaceuticals TCMC mercury-197 Hg radiometals DOTAM |
| title | Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals |
| title_full | Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals |
| title_fullStr | Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals |
| title_full_unstemmed | Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals |
| title_short | Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals |
| title_sort | exploration of commercial cyclen based chelators for mercury 197 m g incorporation into theranostic radiopharmaceuticals |
| topic | radiopharmaceuticals TCMC mercury-197 Hg radiometals DOTAM |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2024.1292566/full |
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