The Cu
2+
complexes formed by a series of cyclen derivatives
bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane
(DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane
(DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane
(DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane
(DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic
and structural points of view to evaluate their potential as chelators
for copper radioisotopes. UV–vis spectrophotometric out-of-cell
titrations under strongly acidic conditions, direct in-cell UV–vis
titrations, potentiometric measurements at pH >4, and spectrophotometric
Ag
+
–Cu
2+
competition experiments were
performed to evaluate the stoichiometry and stability constants of
the Cu
2+
complexes. A highly stable 1:1 metal-to-ligand
complex (CuL) was found in solution at all pH values for all chelators,
and for DO2A2S, protonated species were also detected under acidic
conditions. The structures of the Cu
2+
complexes in aqueous
solution were investigated by UV–vis and electron paramagnetic
resonance (EPR), and the results were supported by relativistic density
functional theory (DFT) calculations. Isomers were detected that differed
from their coordination modes. Crystals of [Cu(DO4S)(NO
3
)]·NO
3
and [Cu(DO2A2S)] suitable for X-ray diffraction
were obtained. Cyclic voltammetry (CV) experiments highlighted the
remarkable stability of the copper complexes with reference to dissociation
upon reduction from Cu
2+
to Cu
+
on the CV time
scale. The Cu
+
complexes were generated in situ by electrolysis
and examined by NMR spectroscopy. DFT calculations gave further structural
insights. These results demonstrate that the investigated sulfur-containing
chelators are promising candidates for application in copper-based
radiopharmaceuticals. In this connection, the high stability of both
Cu
2+
and Cu
+
complexes can represent a key parameter
for avoiding
in vivo
demetalation after bioinduced
reduction to Cu
+
, often observed for other well-known chelators
that can stabilize only Cu
2+
.
