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