Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange Reaction
Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for di...
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MDPI AG
2023-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/12/2749 |
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| author | Austin Craig Jürgen Kogler Markus Laube Martin Ullrich Cornelius K. Donat Robert Wodtke Klaus Kopka Sven Stadlbauer |
| author_facet | Austin Craig Jürgen Kogler Markus Laube Martin Ullrich Cornelius K. Donat Robert Wodtke Klaus Kopka Sven Stadlbauer |
| author_sort | Austin Craig |
| collection | DOAJ |
| description | Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule <sup>18</sup>F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, <b>12</b> and <b>13,</b> were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC<sub>50</sub> 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [<sup>18</sup>F]fluoride exchange ([<sup>18</sup>F]SuFEx) reaction to furnish [<sup>18</sup>F]<b>12</b> and [<sup>18</sup>F]<b>13</b> in high activity yields (AY) of 39–56% and molar activities (A<sub>m</sub>) between 20–55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and <sup>18</sup>F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either <sup>18</sup>F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [<sup>18</sup>F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development. |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-08T20:26:57Z |
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| spelling | doaj.art-664a01d0f78c4972ad7e20ef2c2023c52023-12-22T14:32:13ZengMDPI AGPharmaceutics1999-49232023-12-011512274910.3390/pharmaceutics15122749Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange ReactionAustin Craig0Jürgen Kogler1Markus Laube2Martin Ullrich3Cornelius K. Donat4Robert Wodtke5Klaus Kopka6Sven Stadlbauer7Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, GermanyEarly detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule <sup>18</sup>F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, <b>12</b> and <b>13,</b> were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC<sub>50</sub> 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [<sup>18</sup>F]fluoride exchange ([<sup>18</sup>F]SuFEx) reaction to furnish [<sup>18</sup>F]<b>12</b> and [<sup>18</sup>F]<b>13</b> in high activity yields (AY) of 39–56% and molar activities (A<sub>m</sub>) between 20–55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and <sup>18</sup>F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either <sup>18</sup>F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [<sup>18</sup>F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development.https://www.mdpi.com/1999-4923/15/12/2749automationcancer-associated fibroblastFAPI<sup>18</sup>F fluorinationpositron emission tomography (PET)[<sup>18</sup>F]SuFEx |
| spellingShingle | Austin Craig Jürgen Kogler Markus Laube Martin Ullrich Cornelius K. Donat Robert Wodtke Klaus Kopka Sven Stadlbauer Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange Reaction Pharmaceutics automation cancer-associated fibroblast FAPI <sup>18</sup>F fluorination positron emission tomography (PET) [<sup>18</sup>F]SuFEx |
| title | Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange Reaction |
| title_full | Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange Reaction |
| title_fullStr | Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange Reaction |
| title_full_unstemmed | Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange Reaction |
| title_short | Preparation of <sup>18</sup>F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [<sup>18</sup>F]Fluoride Exchange Reaction |
| title_sort | preparation of sup 18 sup f labeled tracers targeting fibroblast activation protein via sulfur sup 18 sup f fluoride exchange reaction |
| topic | automation cancer-associated fibroblast FAPI <sup>18</sup>F fluorination positron emission tomography (PET) [<sup>18</sup>F]SuFEx |
| url | https://www.mdpi.com/1999-4923/15/12/2749 |
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