Investigation of conditions for oxidation of radiolabelled inverse-electron demand Diels-Alder reaction intermediate products
Novotna, Dominika (2025-04-25)
Investigation of conditions for oxidation of radiolabelled inverse-electron demand Diels-Alder reaction intermediate products
(25.04.2025)
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
suljettu
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2025060257348
https://urn.fi/URN:NBN:fi-fe2025060257348
Tiivistelmä
Positron emission tomography (PET) is a highly sensitive and non-invasive medical imaging technique, which uses radiotracers containing positron emitting isotopes to assess the metabolic activity of tissues. PET is commonly used in drug discovery and in medical imaging applications.
Inverse electron demand Diels-Alder (iEDDA) reaction is the fastest, catalyst-free, irreversible, chemoselective, and consequently, the most used bioorthogonal click reaction in vivo. Tetrazine ligation with trans-cyclooctenes (TCO) is the most common iEDDA reaction, involving a cycloaddition reaction of electron-poor tetrazines and electron-rich trans-cyclooctenes. IEDDA click reactions have displayed great potential to be used in PET either for pretargeted PET imaging or as a radiolabelling method in the production of PET radiopharmaceuticals. In both cases, it is a very useful method for molecules which would otherwise be unsuitable for fluorine-18 radiolabelling conditions.
Tetrazine and TCO ligation used as a radiolabelling method in the production of PET radiopharmaceuticals, however, has a significant drawback caused by the formation of a mixture of reduced metastable dihydropyridazine (DHP) species. Oxidation is required to convert these DHPs to pyridazines which is crucial to simplify quality control and to comply with the requirements for PET tracers, requiring > 95 % purity of the final product. This work was focused on the study of the oxidation rates of DHPs using different external energy inputs: increased temperatures, UV light, and radioactivity.
It was discovered that UV light and radioactivity effectively promoted the oxidation of DHPs to the stable pyridazine, while increased temperatures did not. Evidence supported that increasing the starting radioactivity also increased the rate of oxidation. With 3 GBq and 6 GBq starting radioactivities, a full oxidation was achieved after 240 and 120 minutes, respectively, while 1 GBq reaction did not reach completion even after 287 minutes. UV light resulted in the fastest oxidation rates, achieving full oxidation of DHPs after 10 minutes at room temperature.
Based on these results, radioactivity and UV light demonstrated great efficiency for fast oxidation of DHPs, which could facilitate more efficient PET tracer production methods, significantly advancing PET diagnostics.
Inverse electron demand Diels-Alder (iEDDA) reaction is the fastest, catalyst-free, irreversible, chemoselective, and consequently, the most used bioorthogonal click reaction in vivo. Tetrazine ligation with trans-cyclooctenes (TCO) is the most common iEDDA reaction, involving a cycloaddition reaction of electron-poor tetrazines and electron-rich trans-cyclooctenes. IEDDA click reactions have displayed great potential to be used in PET either for pretargeted PET imaging or as a radiolabelling method in the production of PET radiopharmaceuticals. In both cases, it is a very useful method for molecules which would otherwise be unsuitable for fluorine-18 radiolabelling conditions.
Tetrazine and TCO ligation used as a radiolabelling method in the production of PET radiopharmaceuticals, however, has a significant drawback caused by the formation of a mixture of reduced metastable dihydropyridazine (DHP) species. Oxidation is required to convert these DHPs to pyridazines which is crucial to simplify quality control and to comply with the requirements for PET tracers, requiring > 95 % purity of the final product. This work was focused on the study of the oxidation rates of DHPs using different external energy inputs: increased temperatures, UV light, and radioactivity.
It was discovered that UV light and radioactivity effectively promoted the oxidation of DHPs to the stable pyridazine, while increased temperatures did not. Evidence supported that increasing the starting radioactivity also increased the rate of oxidation. With 3 GBq and 6 GBq starting radioactivities, a full oxidation was achieved after 240 and 120 minutes, respectively, while 1 GBq reaction did not reach completion even after 287 minutes. UV light resulted in the fastest oxidation rates, achieving full oxidation of DHPs after 10 minutes at room temperature.
Based on these results, radioactivity and UV light demonstrated great efficiency for fast oxidation of DHPs, which could facilitate more efficient PET tracer production methods, significantly advancing PET diagnostics.