Synthesis and characterization of the copper(ii) complexes of new N ₂S₂-donor macrocyclic ligands: Synthesis and in vivo evaluation of the ⁶⁴Cu complexes

The aim of this work was to prepare a novel class of ⁶⁴Cu(ii) labeled complexes with the new macrocyclic ligands 1,10-dithia-4,7- diazacyclododecane-3,8-dicarboxylic acid (NEC-SE, 1), 1,10-dithia-4,7- diazacyclotridecane-3,8-dicarboxylic acid (NEC-SP, 2) and 1,10-dithia-4,7- diazacyclotetradecane-3,8-dicarboxylic acid, (NEC-SB, 3) to evaluate the usefulness of these macrocycles for potential utility as ⁶⁴Cu(ii) chelators. The corresponding non-radioactive complexes [Cu(NEC-SE)] ·3H₂O (4), [Cu(NEC-SP)]·3H₂O (5) and [Cu(NEC-SB)] (6) were prepared and their ⁶⁴Cu-analogs, [ ⁶⁴Cu(NEC-SE)] (7) and [⁶⁴Cu(NEC-SP)] (8) and [ ⁶⁴Cu(NEC-SB)] (9) were produced in >98% radiochemical purity. Rats were injected with complex 7, 8 or 9 and were euthanized at 1, 4 and 24 h. All three complexes are cleared from the blood over the first hour following injection but there is poor clearance of this activity over 24 h. A similar pattern of retention was noted in the liver where the levels of activity in this tissue at 1 h are not statistically different from those at 24 h. Molecular mechanics and DFT studies were performed on the complexes in order to gain insight into the lower stability.