Comparative Study of NOTA-Derived Chelators: Synthesis, Al18F/177Lu Radiolabeling and Computational Analysis

The development of hybrid bifunctional chelators (BFCs) capable of efficiently coordinating both diagnostic and therapeutic radionuclides remains a major challenge in theranostic radiopharmaceutical design. Herein, two novel hybrid NOTA-derived chelators, NO2A-2C-AHM and NODAGA-HM, were developed from the previously reported NO2A-AHM BFC to improve the coordination of 177Lu while preserving efficient Al18F labeling. Both ligands were successfully synthesized and fully characterized by NMR and mass spectrometry analyses. Their coordination properties toward {AlF}2+ and Lu3+ were thoroughly investigated by molecular modeling, non-radioactive complexation, and radiolabeling studies. Both chelators efficiently formed AlF complexes, exhibiting high complexation yields and successful Al18F radiolabeling with good stability. In contrast, only NODAGA-HM efficiently coordinated Lu3+, whereas NO2A-2C-AHM failed to form stable Lu complexes under both non-radioactive and radiolabeling conditions. Optimized radiolabeling of NODAGA-HM with 177Lu afforded high radiochemical conversion, consistent with the molecular modeling predictions. These results demonstrate that the spatial positioning of the additional donor arm, rather than linker elongation alone, is a key determinant for efficient coordination of larger trivalent radiometals. Thus, NODAGA-HM emerged as the most promising candidate for further development of targeted radiopharmaceuticals based on the Al18F/177Lu theranostic approach.