2 research outputs found
DataSheet1_Exploration of commercial cyclen-based chelators for mercury-197Â m/g incorporation into theranostic radiopharmaceuticals.PDF
A comprehensive investigation of the Hg2+ coordination chemistry and 197m/gHg radiolabeling capabilities of cyclen-based commercial chelators, namely, DOTA and DOTAM (aka TCMC), along with their bifunctional counterparts, p-SCN-Bn-DOTA and p-SCN-Bn-TCMC, was conducted to assess the suitability of these frameworks as bifunctional chelators for the 197m/gHg2+ theranostic pair. Radiolabeling studies revealed that TCMC and DOTA exhibited low radiochemical yields (0%â6%), even when subjected to harsh conditions (80°C) and high ligand concentrations (10â4 M). In contrast, p-SCN-Bn-TCMC and p-SCN-Bn-DOTA demonstrated significantly higher 197m/gHg radiochemical yields (100% ± 0.0% and 70.9% ± 1.1%, respectively) under the same conditions. The [197 m/gHg]Hg-p-SCN-Bn-TCMC complex was kinetically inert when challenged against human serum and glutathione. To understand the differences in labeling between the commercial chelators and their bifunctional counterparts, non-radioactive natHg2+ complexes were assessed using NMR spectroscopy and DFT calculations. The NMR spectra of Hg-TCMC and Hg-p-SCN-Bn-TCMC suggested binding of the Hg2+ ion through the cyclen backbone framework. DFT studies indicated that binding of the Hg2+ ion within the backbone forms a thermodynamically stable product. However, competition can form between isothiocyanate binding and binding through the macrocycle, which was experimentally observed. The isothiocyanate bound coordination product was dominant at the radiochemical scale as, in comparison, the macrocycle bound product was seen at the NMR scale, agreeing with the DFT result. Furthermore, a bioconjugate of TCMC (TCMC-PSMA) targeting prostate-specific membrane antigen was synthesized and radiolabeled, resulting in an apparent molar activity of 0.089 MBq/nmol. However, the complex demonstrated significant degradation over 24 h when exposed to human serum and glutathione. Subsequently, cell binding assays were conducted, revealing a Ki value ranging from 19.0 to 19.6 nM. This research provides crucial insight into the effectiveness of current commercial chelators in the context of 197m/gHg2+ radiolabeling. It underscores the necessity for the development of specific and customized chelators to these unique âsoftâ radiometals to advance 197m/gHg2+ radiopharmaceuticals.</p
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 ligandâs 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