Recent Advances in Functional Chelators for PET and SPECT Imaging Probes

Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) are two of the most frequently employed molecular imaging modalities for interrogating biological processes in living systems. A significant number of recently developed probes are based on radiometals. Radiometal-based compounds use a chelator for radionuclide complexation and linkage to a targeting molecule. In practice, selecting the "right" chelator has consequences that extend well beyond simple coordination chemistry, influencing labeling conditions, probe stability, in vivo behavior, and ultimately diagnostic performance. As a result, both acyclic and cyclic chelators have been explored extensively. Acyclic chelators, such as DTPA, HBED, DFO, and HYNIC, are attractive because they can be labeled rapidly under mild conditions, but their in vivo stability is not always sufficient for clinical use. In contrast, macrocyclic chelators, such as DOTA, NOTA, TETA, and sarcophagines, are more kinetically inert, though they often demand higher temperatures or more stringent labeling parameters. Over the past decades, several innovations have been made, such as [18F]AlF-NOTA chemistry, optimized DFO derivatives for 89Zr, and copper-specific sarcophagines. This emerging landscape of PET and SPECT radiotracers has broadened the range of applications from neuroendocrine tumors to FAPI-based probes and to theranostic strategies. The refinement and development of bifunctional chelators that allow radiometals to be bound to peptides, antibodies, and nanoparticles without loss of biological activity is opening up new avenues. The field is working toward more kit-based, user-friendly chelators that are applicable to a broad range of radionuclides. In this review, we summarize recent progress in chelator design and show how it is shaping the future of molecular imaging and targeted radionuclide therapy.