Synthesis and characterization of the copper(II) complexes of new N2S2-donor macrocyclic ligands: synthesis and in vivo evaluation of the 64Cu complexes

The aim of this work was to prepare a novel class of Cu-64(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 Cu-64(II) chelators. The corresponding non-radioactive complexes [Cu(NEC-SE)]center dot 3H(2)O (4), [Cu(NEC-SP)]center dot 3H(2)O (5) and [Cu(NEC-SB)] (6) were prepared and their Cu-64-analogs, [Cu-64(NEC-SE)] (7) and [Cu-64(NEC-SP)] (8) and [Cu-64(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.