Radiometal‐Based PET Imaging: Coordination Chemistry as a Determinant of In Vivo Performance

Radiometal‐based positron emission tomography (PET) has become an indispensable tool for molecular imaging, enabling the noninvasive interrogation of biological processes across a broad range of time scales. Despite substantial advances in radionuclide production and targeting vector design, the in vivo performance and quantitative reliability of many radiometal PET tracers remain limited. These shortcomings are frequently attributed to biological factors; however, growing evidence indicates that they originate predominantly from unresolved challenges in coordination chemistry. This review critically examines commonly used PET radiometals, including [ 44 Sc]Sc, [ 64 Cu]Cu, [ 68 Ga]Ga, and [ 89 Zr]Zr, with a particular focus on the role of bifunctional chelating agents in governing metal stability, biodistribution, and imaging fidelity. Rather than providing a catalog of radionuclides and ligands, we identify recurring, cross‐system chemical constraints—such as incomplete metal coordination, insufficient kinetic inertness, and reliance on empirically inherited chelation frameworks—that continue to define the practical limits of radiometal PET. By comparing these systems across different biological time scales, this review highlights how chelator design, more than radionuclide physics alone, dictates translational success. Collectively, these insights underscore the need for mechanistically informed chelator development and standardized evaluation strategies to enable the next generation of robust, quantitative radiometal‐based PET imaging agents.