Cleeren Frederik, Lecina Joan, Billaud Emilie M F, Ahamed Muneer, Verbruggen Alfons, Bormans Guy M
Laboratory for Radiopharmacy, University of Leuven , Herestraat 49 box 821, BE3000 Leuven, Belgium.
Bioconjug Chem. 2016 Mar 16;27(3):790-8. doi: 10.1021/acs.bioconjchem.6b00012. Epub 2016 Feb 25.
The Al(18)F labeling method is a relatively new approach that allows radiofluorination of biomolecules such as peptides and proteins in a one-step procedure and in aqueous solution. However, the chelation of the {Al(18)F}(2+) core with the macrocyclic chelators NOTA or NODA requires heating to 100-120 °C. Therefore, we have developed new polydentate ligands for the complexation of {Al(18)F}(2+) with good radiochemical yields at a temperature of 40 °C. The stability of the new Al(18)F-complexes was tested in phosphate buffered saline (PBS) at pH 7.4 and in rat serum. The stability of the Al(18)F-L3 complex was found to be comparable to that of the previously reported Al(18)F-NODA complex up to 60 min in rat serum. Moreover, the biodistribution of Al(18)F-L3 in healthy mice showed the absence of in vivo defluorination since no significant bone uptake was observed, whereas the major fraction of activity at 60 min p.i. was observed in liver and intestines, indicating hepatobiliary clearance of the radiolabeled ligand. The acyclic chelator H3L3 proved to be a good lead candidate for labeling of heat-sensitive biomolecules with fluorine-18. In order to obtain a better understanding of the different factors influencing the formation and stability of the complex, we carried out more in-depth experiments with ligand H3L3. As a proof of concept, we successfully conjugated the new AlF-chelator with the urea-based PSMA inhibitor Glu-NH-CO-NH-Lys to form Glu-NH-CO-NH-Lys(Ahx)L3, and a biodistribution study in healthy mice was performed with the Al(18)F-labeled construct. This new class of AlF-chelators may have a great impact on PET radiochemical space as it will stimulate the rapid development of new fluorine-18 labeled peptides and other heat-sensitive biomolecules.
Al(18)F标记方法是一种相对较新的方法，它能够在一步操作中且在水溶液中对诸如肽和蛋白质等生物分子进行放射性氟化。然而，{Al(18)F}(2+)核心与大环螯合剂NOTA或NODA的螯合需要加热至100 - 120°C。因此，我们开发了新的多齿配体，用于在40°C的温度下以良好的放射化学产率使{Al(18)F}(2+)络合。在pH 7.4的磷酸盐缓冲盐水（PBS）和大鼠血清中测试了新型Al(18)F络合物的稳定性。发现在大鼠血清中，Al(18)F - L3络合物的稳定性在长达60分钟的时间内与先前报道的Al(18)F - NODA络合物相当。此外，Al(18)F - L3在健康小鼠体内的生物分布表明不存在体内脱氟现象，因为未观察到明显的骨摄取，而在注射后60分钟时，大部分活性在肝脏和肠道中被观察到，表明放射性标记配体通过肝胆途径清除。无环螯合剂H3L3被证明是用氟 - 18标记热敏生物分子的良好先导候选物。为了更好地理解影响络合物形成和稳定性的不同因素，我们用配体H3L3进行了更深入的实验。作为概念验证，我们成功地将新型AlF螯合剂与基于尿素的PSMA抑制剂Glu - NH - CO - NH - Lys偶联，形成Glu - NH - CO - NH - Lys(Ahx)L3，并对Al(18)F标记的构建体在健康小鼠中进行了生物分布研究。这类新型AlF螯合剂可能会对PET放射化学领域产生重大影响，因为它将推动新型氟 - 18标记肽和其他热敏生物分子的快速发展。
