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

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Abstract

[68 Ga]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 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 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 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.

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