HNODThia: A Promising Chelator for the Development of ⁶⁴Cu Radiopharmaceuticals

Area of Science:

• Coordination Chemistry
• Radiopharmaceutical Development
• Nuclear Medicine

Background:

• Development of novel chelating agents is crucial for stable radiometal complex formation.
• Triazacyclononane (tacn)-based ligands offer promising coordination properties for radiometals.
• Efficient methods for radiolabeling biomolecules are essential for targeted radio(immuno)therapy.

Purpose of the Study:

• To synthesize and characterize novel tacn-based chelators for copper-64 (⁶⁴Cu) radiopharmaceuticals.
• To develop a bifunctional photoactivatable chelator for light-induced radiolabeling of proteins.
• To evaluate the stability and efficiency of developed radiolabeling strategies.

Main Methods:

• Synthesis of H NODThia and NODThia-AcNHEt chelators and their metal complexes.
• Derivatization of H NODThia to NODThia-PSMA and NODThia-PEG-ArN.
• ⁶⁴Cu radiolabeling of chelates, stability studies in human plasma, and photo-induced conjugation to proteins (HSA, MetMAb).

Main Results:

• Quantitative radiochemical conversion (>95% RCP) achieved in <10 min at room temperature for ⁶⁴Cu labeling.
• Stable ⁶⁴Cu radiolabeling of NODThia-PSMA demonstrated through in vitro assays.
• Efficient photo-induced radiolabeling of human serum albumin and MetMAb with ⁶⁴Cu in <15 min.

Conclusions:

• Novel tacn-based chelators provide a robust platform for developing stable ⁶⁴Cu radiopharmaceuticals.
• Photoactivatable chelators enable rapid light-induced radiolabeling of proteins and antibodies.
• This approach holds significant potential for advancing molecularly targeted radio(immuno)therapy with ⁶⁴Cu and ⁶⁷Cu.