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

Helen Damerow; Björn Wängler; Ralf Schirrmacher; Gert Fricker; Carmen Wängler

doi:10.1002/cmdc.202200495

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

ChemMedChem. 2023 Jan 3;18(1):e202200495. doi: 10.1002/cmdc.202200495. Epub 2022 Nov 7.

Authors

Helen Damerow¹, Björn Wängler², Ralf Schirrmacher³, Gert Fricker⁴, Carmen Wängler¹

Affiliations

¹ Clinic of Radiology and Nuclear Medicine, Biomedical Chemistry, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.
² Clinic of Radiology and Nuclear Medicine, Molecular Imaging and Radiochemistry, Medical Faculty Mannheim of Heidelberg University, 68167, Mannheim, Germany.
³ Department of Oncology, Division of Oncological Imaging, University of Alberta, Edmonton, AB, T6G 1Z2, Canada.
⁴ Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120, Heidelberg, Germany.

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.

Keywords: 68Ga; CB-DO2A-GA; peptide conjugation; radiochemistry; radiolabeling efficiency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chelating Agents*
Peptides
Peptides, Cyclic / metabolism
Positron-Emission Tomography* / methods

Substances

Chelating Agents
Peptides
Peptides, Cyclic