New Tc-99m(CO)(3) Mannosylated Dextran Bearing S-Derivatized Cysteine Chelator for Sentinel Lymph Node Detection
authors Pirmettis, I; Arano, Y; Tsotakos, T; Okada, K; Yamaguchi, A; Uehara, T; Morais, M; Correia, JDG; Santos, I; Martins, M; Pereira, S; Triantis, C; Kyprianidou, P; Pelecanou, M; Papadopoulos, M
nationality International
journal MOLECULAR PHARMACEUTICS
author keywords Tc-99m; Re; dextran; mannose; cysteine; sentinel lymph node
keywords CLICK CHEMISTRY; BREAST-CANCER; LIGANDS; RADIOPHARMACEUTICALS; COMPLEXES; TC-99M; ACIDS
abstract The aim of the present study is to synthesize new mannosylated dextran derivative that can be labeled with Tc-99m for potential use in sentinel lymph node detection (SLND). The compound was designed to have a dextran with molecular weight of 10 kDa as a backbone, mannose for binding to mannose receptors of the lymph node and S-derivatized cysteine as a suitable chelator for labeling with [Tc-99m(H2O)(3)(CO)(3)](+) precursor. Reaction of allyl bromide with dextran (MW 11800) yielded the intermediate allyl-dextran (1) with about 40% coupling. Addition of cysteine to allyl-dextran resulted in the S-derivatized cysteine, compound DC15 (2). The final product DCM20 (3) was obtained in good yield after in situ hydrolysis and activation of cyanomethyl tetraacetyl-1-thio-D-mannopyranoside and coupling to DC15. All derivatives were purified by ultrafiltration and characterized by NMR. DC15 and DCM20 were quantitatively labeled with Tc-99m (>95% radiochemical purity) using the fac-[Tc-99m(OH2)(3)(CO)(3)](+) precursor and ligand concentration of 1.5 x 10(-6) M at neutral pH. Both Tc-99m-labeled compounds Tc-99m(CO)(3)-DC15 (6) and Tc-99m(CO)(3)-DCM20 (7) remained stable after 6 h incubation at 37 degrees C in the presence of excess histidine or cysteine, as well as even after 20-fold dilution and incubation for 24 h at room temperature. The characterization of the compounds 6 and 7 was performed by comparing their HPLC radiochromatograms with those of their rhenium surrogates Re(CO)(3)-DC15 (4) and Re(CO)(3)-DCM20 (5) respectively that were prepared using the precursor [NEt4](2)fac-[ReBr3(CO)(3)] and characterized by IR and NMR spectroscopy. When injected subcutaneously from the foot pad of mice, Tc-99m-labeled mannosylated dextran (7) showed accumulation in the popliteal lymph node (SLN in this model) higher than that of non-mannosylated analogue (6) and the Tc-99m-phytate serving as standard. Compound 7 also exhibited lower radioactivity levels at the injection site compared to Tc-99m-phytate. The SPECT/CT studies in mice confirmed that 7 accumulated in the popliteal lymph node allowing its dear visualization. The present findings demonstrate that compound 7 (Tc-99m(CO)(3)-DCM20) is promising and merits further evaluation as a radiopharmaceutical for sentinel lymph node detection.
publisher AMER CHEMICAL SOC
issn 1543-8384
year published 2012
volume 9
issue 6
beginning page 1681
ending page 1692
digital object identifier (doi) 10.1021/mp300015s
web of science category Medicine, Research & Experimental; Pharmacology & Pharmacy
subject category Research & Experimental Medicine; Pharmacology & Pharmacy
unique article identifier WOS:000304728700015
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journal analysis (jcr 2019):
journal impact factor 4.321
5 year journal impact factor 4.54
category normalized journal impact factor percentile 77.617
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