Stability Estimation of Gallium Complexes of DOTA Derivatives for Radiotheranostic Applications

Area of Science:

• Radiochemistry and Nuclear Medicine
• Chelation Chemistry
• Molecular Imaging

Background:

• 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid (DO3A) is used for ⁶⁸Ga-labeled probes in radiotheranostics.
• While DO3A complexes are stable with therapeutic radionuclides, ⁶⁸Ga-DO3A requires improved in vivo stability.
• The high stability of intact Ga-DOTA complexes motivates the study of DOTA and DO3A derivatives.

Purpose of the Study:

• To evaluate the stability of Ga complexes of DOTA and DO3A derivatives.
• To gain fundamental knowledge for developing next-generation ⁶⁸Ga radiotheranostic probes.
• To assess the impact of structural modifications on complex stability and coordination geometry.

Main Methods:

• Complexation of ⁶⁷Ga with DOTA and DO3A derivatives, including benzyl-DOTA (Bn-DOTA).
• In vitro stability assessment using murine plasma and apo-transferrin challenge.
• X-ray crystallography to determine coordination geometry; conjugation with [Tyr³]octreotide (TOC) for in vivo evaluation.

Main Results:

• [⁶⁷Ga]Ga-Bn-DOTA formed two isomers, with one exhibiting superior stability.
• X-ray crystallography revealed differing coordination geometries (N₃O₃ vs. N₄O₂) impacting stability.
• The ⁶⁷Ga-labeled DOTA-Bn-TOC conjugate showed significantly higher in vitro and in vivo stability than [⁶⁷Ga]Ga-DOTATOC.

Conclusions:

• Para-substituted Bn-DOTA derivatives are promising chelators for next-generation ⁶⁸Ga radiotheranostic probes.
• Coordination geometry significantly influences the stability of Ga complexes.
• Further chemical modifications are needed to prevent less stable N₃O₃ configurations and optimize purification.