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

[(68) Ga]Ga(3+) 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 (68) Ga-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 Tyr(3) -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 (68) Ga-incorporation. Regarding the hydrophilicity profile of the resulting radiopeptides, a decrease in hydrophilicity from [(68) Ga]Ga-DOTA-GA-TATE (log(D(7.4)) of -4.11±0.11) to [(68) Ga]Ga-CB-DO2A-GA-TATE (-3.02±0.08) was observed. Assessing the stability against metabolic degradation and complex challenge, [(68) Ga]Ga-CB-DO2A-GA demonstrated a very high kinetic inertness, exceeding that of [(68) Ga]Ga-DOTA-GA. Therefore, CB-DO2A-GA is a valuable alternative to established chelating agents for (68) Ga-radiolabeling of peptides, especially when the formation of a very stable, positively charged (68) Ga-complex is pursued.