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.