1 research outputs found
Tuning the Framework of Thioether-Functionalized Polyazamacrocycles: Searching for a Chelator for Theranostic Silver Radioisotopes
Silver-111
is an attractive unconventional candidate
for targeted
cancer therapy as well as for single photon emission computed tomography
and can be complemented by silver-103 for positron emission tomography
noninvasive diagnostic procedures. However, the shortage of chelating
agents capable of forming stable complexes tethered to tumor-seeking
vectors has hindered their in vivo application so
far. In this study, a comparative investigation of a series of sulfur-containing
structural homologues, namely, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane
(NO3S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane
(TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclotridecane
(TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetraazacyclotetradecane
(TE4S) was conducted to appraise the influence of different polyazamacrocyclic
backbones on Ag+ complexation. The performances of these
macrocycles were also compared with those of the previously reported
Ag+/[111Ag]Ag+-chelator 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane
(DO4S). Nuclear magnetic resonance data supported by density functional
theory calculations and X-ray crystallographic results gave insights
into the coordination environment of these complexes, suggesting that
all of the donor atoms are generally involved in the metal coordination.
However, the modifications of the macrocycle topology alter the dynamic
binding of the pendant arms or the conformation of the ring around
the metal center. Combined pH/pAg-potentiometric and spectroscopic
experiments revealed that the 12-member N4 backbone of
DO4S forms the most stable Ag+ complex while both the enlargement
and the shrinkage of the macrocyclic frame dwindle the stability of
the complexes. Radiolabeling experiments, conducted with reactor-produced
[111Ag]Ag+, evidenced that the thermodynamic
stability trend is reflected in the ligandās ability to incorporate
the radioactive ion at high molar activity, even in the presence of
a competing cation (Pd2+), as well as in the integrity
of the corresponding complexes in human serum. As a consequence, DO4S
proved to be the most favorable candidate for future in vivo applications