Revisiting dithiadiaza macrocyclic chelators for copper-64 PET imaging.

Area of Science:

• Coordination Chemistry
• Radiopharmaceutical Chemistry
• Computational Chemistry

Background:

• Dithiadiaza chelators offer unique coordination environments for metal ions.
• Copper isotopes, particularly 64Cu, are valuable for diagnostic imaging (PET/MRI).
• Chelator stability is crucial for effective in vivo radiopharmaceutical performance.

Purpose of the Study:

• To synthesize and characterize a novel dithiadiaza chelator, NSNS2A.
• To investigate the solution structures and stability of copper(I/II) complexes with NSNS2A.
• To evaluate the in vivo stability and biodistribution of a 64Cu-labeled NSNS2A complex for PET/MRI applications.

Main Methods:

• Synthesis and characterization of the NSNS2A chelator.
• Density Functional Theory (DFT) calculations for structural analysis.
• Nuclear Magnetic Resonance (NMR) and Electron Paramagnetic Resonance (EPR) spectroscopy for validation.
• Radiolabeling with 64Cu and in vivo evaluation using Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in rats.

Main Results:

• DFT calculations predicted a switch in tetragonal distortion upon protonation, correlating with experimental observations of solvent-dependent structural changes.
• The 64Cu(II)NSNS2A complex exhibited suboptimal in vivo stability compared to the 64Cu(TE2A) analogue.
• Significant 64Cu uptake was observed in the liver, indicating limited stability and potential off-target accumulation.

Conclusions:

• The NSNS2A chelator and its copper complexes were successfully synthesized and characterized.
• Structural insights from DFT and spectroscopy explain the observed instability of the copper(II) complex in aqueous media.
• The 64Cu(II)NSNS2A complex demonstrated insufficient in vivo stability for effective PET/MRI, highlighting the importance of chelator design for radiopharmaceutical development.