New Chelators for Low Temperature Al18F-Labeling of Biomolecules

The (AlF)-F-18 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 {(AlF)-F-18}(2+) core with the macrocyclic chelators NOTA or NODA requires heating to 100-120 degrees C. Therefore, we have developed new polydentate ligands for the complexation of {(AlF)-F-18}(2+) with good radiochemical yields at a temperature of 40 degrees C. The stability of the new (AlF)-F-18-complexes was tested in phosphate buffered saline (PBS) at pH 7.4 and in rat serum. The stability of the (AlF)-F-18-L3 complex was found to be comparable to that of the previously reported (AlF)-F-18-NODA complex up to 60 min in rat serum. Moreover, the biodistribution of (AlF)-F-18-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 H(3)L3 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 H(3)L3. As a proof of concept, we successfully conjugated the new AIF-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 (AlF)-F-18-labeled construct. This new class of AIF-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.