Synthesis of a Bifunctional Cross‐Bridged Chelating Agent, Peptide Conjugation, and Comparison of 68Ga Labeling and Complex Stability Characteristics with Established Chelators

Abstract [68Ga]Ga3+ can be introduced into receptor‐specific peptidic carriers via different chelators to obtain radiotracers for Positron Emission Tomography imaging and the chosen chelating agent considerably influences the in vivo pharmacokinetics of the corresponding radiopeptides. A chelator that should be a valuable alternative to established chelating agents for 68Ga‐radiolabeling of peptides would be a backbone‐functionalized variant of the chelator CB‐DO2A. Here, the bifunctional cross‐bridged chelating agent CB‐DO2A‐GA was developed and compared to the established chelators DOTA, NODA‐GA and DOTA‐GA. For this purpose, CB‐DO2A‐GA(tBu)2 was introduced into the peptide Tyr3‐octreotate (TATE) and in direct comparison to the corresponding DOTA‐, NODA‐GA‐, and DOTA‐GA‐modified TATE analogs, CB‐DO2A‐GA‐TATE required harsher reaction conditions for 68Ga‐incorporation. Regarding the hydrophilicity profile of the resulting radiopeptides, a decrease in hydrophilicity from [68Ga]Ga‐DOTA‐GA‐TATE (logD(7.4) of −4.11±0.11) to [68Ga]Ga‐CB‐DO2A‐GA‐TATE (−3.02±0.08) was observed. Assessing the stability against metabolic degradation and complex challenge, [68Ga]Ga‐CB‐DO2A‐GA demonstrated a very high kinetic inertness, exceeding that of [68Ga]Ga‐DOTA‐GA. Therefore, CB‐DO2A‐GA is a valuable alternative to established chelating agents for 68Ga‐radiolabeling of peptides, especially when the formation of a very stable, positively charged 68Ga‐complex is pursued.