Kramer Carsten Sven, Greiner Luca, Kopka Klaus, Schäfer Martin
Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 223, 69120, Heidelberg, Germany.
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR) e. v., Bautzner Landstrasse 400, 01328, Dresden, Germany.
EJNMMI Radiopharm Chem. 2022 Jun 25;7(1):15. doi: 10.1186/s41181-022-00167-y.
Positron emission tomography (PET) is a powerful tool in medical imaging, especially in combination with the PET radionuclide fluorine-18 that possesses optimal characteristics. For labelling of biomolecules and low-molecular weight tracers, fluorine-18 can be covalently bound to silicon by either nucleophilic replacements of leaving groups (like ethers) or by isotope exchange of fluorine-19. While nucleophilic substitutions require additional purification steps for the removal of contaminants, isotope exchange with fluorine-18 results in low molar activity. Both challenges can be addressed with a detagging-fluorination of an immobilized silyl ether motif.
By overcoming the susceptibility towards hydrolysis, optimized detagging conditions (improved reaction time, fluorination reagent, linker, and resin) could afford the highly sterically hindered silyl fluoride motifs, that are commonly applied in radiochemistry in small and semipreparative scales. The described reaction conditions with fluorine-19 are transferrable to conditions with [F]fluoride and silyl fluorides were obtained after approx. 10 min reaction time and in high-purity after mechanical filtration.
We present a proof-of-concept study for a detagging-fluorination of two silyl ethers that are bound to an optimized amino alcohol resin. We show with our model substrate that our solid-phase linker combination is capable of yielding the desired silicon fluoride in amounts sufficient for biological studies in animals or humans under standard fluorination conditions that may also be transferred to a radiolabelling setting. In conclusion, our presented approach could optimize the molar activity and simplify the preparation of radiofluorinated silyl fluorides.
正电子发射断层扫描（PET）是医学成像中的一种强大工具，特别是与具有最佳特性的PET放射性核素氟-18结合使用时。对于生物分子和低分子量示踪剂的标记，氟-18可以通过离去基团（如醚）的亲核取代或氟-19的同位素交换与硅共价结合。虽然亲核取代需要额外的纯化步骤来去除污染物，但与氟-18的同位素交换会导致低摩尔活性。通过固定化甲硅烷基醚基序的去标记氟化可以解决这两个挑战。
通过克服水解敏感性，优化的去标记条件（改进的反应时间、氟化试剂、连接体和树脂）可以得到高度空间位阻的甲硅烷基氟基序，这些基序通常用于放射化学的小规模和半制备规模。所描述的与氟-19的反应条件可转移到使用[F]氟化物的条件下，反应约10分钟后得到甲硅烷基氟，经机械过滤后纯度很高。
我们展示了一项针对两种与优化的氨基醇树脂结合的甲硅烷基醚进行去标记氟化的概念验证研究。我们用模型底物表明，我们的固相连接体组合能够在标准氟化条件下产生足以用于动物或人体生物学研究的所需甲硅烷氟化物量，这些条件也可转移到放射性标记环境中。总之，我们提出的方法可以优化摩尔活性并简化放射性氟化甲硅烷基氟化物的制备。
