Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET
Abstract Background The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific ant...
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SpringerOpen
2024-03-01
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| Series: | EJNMMI Radiopharmacy and Chemistry |
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| Online Access: | https://doi.org/10.1186/s41181-024-00250-6 |
| _version_ | 1797266586258636800 |
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| author | Eva Schlein Johanna Rokka Luke R. Odell Sara Lopes van den Broek Matthias M. Herth Umberto M. Battisti Stina Syvänen Dag Sehlin Jonas Eriksson |
| author_facet | Eva Schlein Johanna Rokka Luke R. Odell Sara Lopes van den Broek Matthias M. Herth Umberto M. Battisti Stina Syvänen Dag Sehlin Jonas Eriksson |
| author_sort | Eva Schlein |
| collection | DOAJ |
| description | Abstract Background The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging. A viable solution could be a two-step pre-targeting approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a small radiolabelled molecule with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved by using the inverse electron demand Diels–Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants. In this study, two novel 18F-labelled tetrazines were synthesized and evaluated for their potential use as pre-targeting imaging agents, i.e., for their ability to rapidly enter the brain and, if unbound, to be efficiently cleared with minimal background retention. Results The two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans showed [18F]MeTz to be the more pharmacokinetically suitable agent, given its fast and homogenous distribution in the brain and rapid clearance. However, in terms of rection kinetics, H-tetrazines are advantageous, exhibiting faster reaction rates in IEDDA reactions with dienophiles like trans-cyclooctenes, making [18F]HTz potentially more beneficial for pre-targeting applications. Conclusion This study demonstrates a significant potential of [18F]MeTz and [18F]HTz as agents for pre-targeted PET brain imaging due to their efficient brain uptake, swift clearance and appropriate chemical stability. |
| first_indexed | 2024-04-25T01:03:03Z |
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| institution | Directory Open Access Journal |
| issn | 2365-421X |
| language | English |
| last_indexed | 2024-04-25T01:03:03Z |
| publishDate | 2024-03-01 |
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| spelling | doaj.art-b44e94073a1c42c6b15c9f32f6ffe3792024-03-10T12:24:46ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2024-03-019111210.1186/s41181-024-00250-6Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PETEva Schlein0Johanna Rokka1Luke R. Odell2Sara Lopes van den Broek3Matthias M. Herth4Umberto M. Battisti5Stina Syvänen6Dag Sehlin7Jonas Eriksson8Department of Public Health and Caring Sciences, Uppsala UniversityDepartment of Public Health and Caring Sciences, Uppsala UniversityDepartment of Medicinal Chemistry, Uppsala UniversityDepartment of Public Health and Caring Sciences, Uppsala UniversityDepartment of Drug Design and Pharmacology, University of CopenhagenDepartment of Drug Design and Pharmacology, University of CopenhagenDepartment of Public Health and Caring Sciences, Uppsala UniversityDepartment of Public Health and Caring Sciences, Uppsala UniversityDepartment of Medicinal Chemistry, Uppsala UniversityAbstract Background The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging. A viable solution could be a two-step pre-targeting approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a small radiolabelled molecule with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved by using the inverse electron demand Diels–Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants. In this study, two novel 18F-labelled tetrazines were synthesized and evaluated for their potential use as pre-targeting imaging agents, i.e., for their ability to rapidly enter the brain and, if unbound, to be efficiently cleared with minimal background retention. Results The two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans showed [18F]MeTz to be the more pharmacokinetically suitable agent, given its fast and homogenous distribution in the brain and rapid clearance. However, in terms of rection kinetics, H-tetrazines are advantageous, exhibiting faster reaction rates in IEDDA reactions with dienophiles like trans-cyclooctenes, making [18F]HTz potentially more beneficial for pre-targeting applications. Conclusion This study demonstrates a significant potential of [18F]MeTz and [18F]HTz as agents for pre-targeted PET brain imaging due to their efficient brain uptake, swift clearance and appropriate chemical stability.https://doi.org/10.1186/s41181-024-00250-6Inverse electron demand Diels–Alder reactionIEDDAPre-targetingTetrazineTrans-cycloocteneTCO |
| spellingShingle | Eva Schlein Johanna Rokka Luke R. Odell Sara Lopes van den Broek Matthias M. Herth Umberto M. Battisti Stina Syvänen Dag Sehlin Jonas Eriksson Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET EJNMMI Radiopharmacy and Chemistry Inverse electron demand Diels–Alder reaction IEDDA Pre-targeting Tetrazine Trans-cyclooctene TCO |
| title | Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET |
| title_full | Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET |
| title_fullStr | Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET |
| title_full_unstemmed | Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET |
| title_short | Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET |
| title_sort | synthesis and evaluation of fluorine 18 labelled tetrazines as pre targeting imaging agents for pet |
| topic | Inverse electron demand Diels–Alder reaction IEDDA Pre-targeting Tetrazine Trans-cyclooctene TCO |
| url | https://doi.org/10.1186/s41181-024-00250-6 |
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