Synthesis of a new bifunctional cross-bridged chelating agent, peptide conjugation, and comparison of 68Ga-labeling and complex stability characteristics with established chelators

19.10.2022

Damerow H, Wängler B, Schirrmacher R, Fricker G, Wängler C* (2023) Synthesis of a new bifunctional cross-bridged chelating agent, peptide conjugation, and comparison of 68Ga-labeling and complex stability characteristics with established chelators. ChemMedChem 18(1), e202200495. DOI: 10.1002/cmdc.202200495.

Graphical Abstract

The new backbone-modified bifunctional cross-bridged chelating agent CB-DO2A-GA was developed, introduced into the peptide Tyr3-octreotate and compared to the established chelators DOTA, NODA-GA and DOTA-GA in terms of 68Ga-radiolabeling efficiency and kinetic inertness of the formed complexes.

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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.