Influences of Ring Sizes and Chiral Substituents on Macrocyclic Chelators for Improving ⁶⁸ Ga Radiolabeling

⁶⁸Ga-labeled macrocyclic ligands have been extensively studied and used for positron emission tomography (PET) imaging. Compared with 12-membered DOTA derivatives, NOTA-based chelators with 9-membered macrocyclic rings exhibit more advantageous coordination stability for Ga³⁺ ions. However, studies of the 10-membered DETA macrocycle are still quite limited. Here, we present the synthesis of four different-sized chiral macrocyclic ligands <b>L1-L4</b>, followed by radiolabeling and stability studies to reveal the influence of ring size and chiral substituents on Ga³⁺ chelation. In the ⁶⁸Ga radiolabeling experiments, chiral NOTA <b>L1</b> exhibits the highest radiochemical yield of 99% at 25 °C. While for the chiral DETA <b>L2</b>/<b>L3</b> and the chiral DOTA <b>L4</b>, their radiolabeling efficiencies are inferior at room temperature, but remarkable improvements were observed at higher temperatures. <b>L1-L4</b> all exhibit superior Ga³⁺ coordination stability than their achiral counterparts, while the chiral DETA <b>L2</b> with an α-methyl group shows a slightly better performance than its β-analogue <b>L3</b>. Serum stability tests and kinetic studies under acid and alkaline conditions were conducted, highlighting the favorable kinetic inertness of these chiral ligands for potential ⁶⁸Ga-labeled PET imaging applications.