Revisiting dithiadiaza macrocyclic chelators for copper-64 PET imaging

Abstract

Synthesis and characterisation of a dithiadiaza chelator NSNS2A, as well as copper complexes thereof are reported in this paper. Solution structures of copper(I/II) complexes were calculated using density functional theory (DFT) and validated by both NMR and EPR spectroscopy. DFT calculations revealed a switch in the orientation of tetragonal distortion upon protonation, which might be responsible for poor stability of the Cu^(II)NSNS2A complex in aqueous media, whilst the same switch in tetragonal distortion was experimentally observed by changing the solvent. The chelator was radiolabeled with ⁶⁴Cu and evaluated using PET/MRI in rats. Despite a favorable redox potential to stabilize the cuprous state in vivo, the ⁶⁴Cu^(II)NSNS2A complex showed suboptimal stability compared to its tetraazamacrocyclic analogue, ⁶⁴Cu(TE2A), with a significant ⁶⁴Cu uptake in the liver.