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

Abstract

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 Garadiolabeling of peptides would be a backbone-functionalized variant of the chelator CB-DO2A. Here, the bifunctional crossbridged 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-modi-fied 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 À 4.11 � 0.11) to [ 68 Ga]Ga-CB-DO2A-GA-TATE (À 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 Gacomplex is pursued.

Advances in macrocyclic chelators for positron emission tomography imaging

“…Cross‐bridged DOTA, CB‐DO2A, confirmed complete envelopment of the central Ga 3+ ion with more ideal bond distances and bond angles than DOTA 37 . Bifunctional variant of CB‐DO2A, namely, CB‐DO2A‐GA was developed by Damerow et al., and demonstrated a very high kinetic inertness against degradation in human serum of the resulting 68 Ga complex 38 . Using glutaric acid in the CB‐DO2A as conjugation arm enables conjugation to Tyr 3 ‐octreotate (TATE) without alteration of coordination sphere 39,40 …”

“…37 Bifunctional variant of CB-DO2A, namely, CB-DO2A-GA was developed by Damerow et al, and demonstrated a very high kinetic inertness against degradation in human serum of the resulting 68 Ga complex. 38 Using glutaric acid in the CB-DO2A as conjugation arm enables conjugation to Tyr 3 -octreotate (TATE) without alteration of coordination sphere. 39,40 The DOTA derivative, PCTA (3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), originally investigated with lanthanides for use as a potential MRI relaxation agent, is a vast improvement over DOTA for 67/68 Ga-radiotracers.…”