Tuning the Properties of Rigidified Acyclic DEDPA^2- Derivatives for Application in PET Using Copper-64

Area of Science:

• Coordination Chemistry
• Radiopharmaceutical Chemistry
• Inorganic Chemistry

Background:

• Copper isotopes, particularly 64Cu, are valuable for medical imaging and therapy.
• Developing stable chelating agents for radiometals is essential for effective radiopharmaceutical design.
• The H2DEDPA ligand framework offers potential for coordinating radiocopper.

Purpose of the Study:

• To synthesize and characterize novel H2DEDPA derivatives with varying cyclic alkyl spacers (cyclohexyl, cyclopentyl, cyclobutyl).
• To investigate the coordination chemistry, stability, and labeling efficiency of these derivatives with natCu/64Cu.
• To explore the potential of a functionalized derivative for bioconjugation.

Main Methods:

• Synthesis of H2DEDPA derivatives (H2CHXDEDPA, H2CpDEDPA, H2CBuDEDPA) and a Boc-protected analogue.
• X-ray crystallography to determine the solid-state structure of Cu(II) complexes.
• Cyclic voltammetry to study redox properties.
• Thermodynamic stability measurements (log KCuL).
• Kinetic dissociation studies under varying pH conditions.
• Radiolabeling studies with 64CuCl2 and assessment of radiochemical purity and stability.

Main Results:

• X-ray structures revealed distorted octahedral coordination of Cu(II) ions.
• Complexes exhibited high thermodynamic stability (log KCuL up to 25.11).
• Dissociation kinetics indicated both spontaneous and proton-assisted pathways at physiological pH.
• Quantitative radiolabeling with 64Cu was achieved rapidly and efficiently for all derivatives.
• The resulting 64Cu-radiocomplexes demonstrated excellent stability in PBS for 24 hours.

Conclusions:

• The investigated H2DEDPA derivatives form highly stable copper complexes.
• These ligands are suitable for rapid and efficient radiolabeling with 64Cu, forming stable radiometal complexes.
• The Boc-protected derivative offers a platform for developing targeted 64Cu-based radiopharmaceuticals.