Development of18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging
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Pretargeted PET imaging is an emerging and fast-developing method to monitor immunooncology strategies. Currently, tetrazine ligation is considered the most promising bioorthogonal reaction for pretargeting in vivo. Recently, we have developed a method to18F-label ultrareactive tetrazines by copper-mediated fluorinations. However, bispyridyl tetrazines—one of the most promising structures for in vivo pretargeted applications—were inaccessible using this strategy. We believed that our successful efforts to18F-label H-tetrazines using low basic labeling conditions could also be used to label bispyridyl tetrazines via aliphatic nucleophilic substitution. Here, we report the first direct18F-labeling of bispyridyl tetrazines, their optimization for in vivo use, as well as their successful application in pretargeted PET imaging. This strategy resulted in the design of [18F]45, which could be labeled in a satisfactorily radiochemical yield (RCY = 16%), molar activity (Am = 57 GBq/µmol), and high radiochemical purity (RCP > 98%). The [18F]45 displayed a target-to-background ratio comparable to previously successfully applied tracers for pretargeted imaging. This study showed that bispyridyl tetrazines can be developed into pretargeted imaging agents. These structures allow an easy chemical modification of18F-labeled tetrazines, paving the road toward highly functionalized pretargeting tools. Moreover, bispyridyl tetrazines led to near-instant drug release of iTCO-tetrazine-based ‘click-to-release’ reactions. Consequently,18F-labeled bispyridyl tetrazines bear the possibility to quantify such release in vivo in the future.
| Original language | English |
|---|---|
| Article number | 245 |
| Journal | Pharmaceuticals |
| Volume | 15 |
| Issue number | 2 |
| Number of pages | 28 |
| ISSN | 1424-8247 |
| DOIs | |
| Publication status | Published - 2022 |
Bibliographical note
Funding Information:
This project received funding from the European Union?s EU Framework Programme for Research and Innovation Horizon 2020 under grant agreement no. 668,532, and from the European Union?s Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement no. 813528. A.K. and M.M.H. received funding from the European Union?s EU Framework Programme for Research and Innovation Horizon 2020 (grant agreement no. 670261). V.S. was supported by the Lundbeck Foundation (R303-2018-3567) and by the BRIDGE Translational Excellence Programme at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation (grant agreement no. NNF18SA0034956). The Lundbeck Foundation, theNovo Nordisk Foundation, the Innovation Fund Denmark, and the Research Council for Independent Research (grant agreement no. 8022-00187B) are further acknowledged.The modified antibody used in this study was kindly provided by Tagworks Pharmaceuticals.
Funding Information:
Funding: This project received funding from the European Union’s EU Framework Programme for Research and Innovation Horizon 2020 under grant agreement no. 668,532, and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 813528. A.K. and M.M.H. received funding from the European Union’s EU Framework Programme for Research and Innovation Horizon 2020 (grant agreement no. 670261). V.S. was supported by the Lundbeck Foundation (R303-2018-3567) and by the BRIDGE Translational Excellence Programme at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation (grant agreement no. NNF18SA0034956). The Lundbeck Foundation, the Novo Nordisk Foundation, the Innovation Fund Denmark, and the Research Council for Independent Research (grant agreement no. 8022-00187B) are further acknowledged.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
- Bioorthogonal chemistry, Bispyridyl tetrazines, Fluorine-18, Molecular imaging, PET, Pretargeted imaging, Tetrazine ligation
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