title: New (99m)Tc(CO)(3) mannosylated dextran bearing S-derivatized cysteine chelator for sentinel lymph node detection.
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 [(99m)Tc(H(2)O)(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 (99m)Tc (>95% radiochemical purity) using the fac-[(99m)Tc(OH(2))(3)(CO)(3)](+) precursor and ligand concentration of 1.5 × 10(-6) M at neutral pH. Both (99m)Tc-labeled compounds (99m)Tc(CO)(3)-DC15 (6) and (99m)Tc(CO)(3)-DCM20 (7) remained stable after 6 h incubation at 37 °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 [NEt(4)](2)fac-[ReBr(3)(CO)(3)] and characterized by IR and NMR spectroscopy. When injected subcutaneously from the foot pad of mice, (99m)Tc-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 (99m)Tc-phytate serving as standard. Compound 7 also exhibited lower radioactivity levels at the injection site compared to (99m)Tc-phytate. The SPECT/CT studies in mice confirmed that 7 accumulated in the popliteal lymph node allowing its clear visualization. The present findings demonstrate that compound 7 ((99m)Tc(CO)(3)-DCM20) is promising and merits further evaluation as a radiopharmaceutical for sentinel lymph node detection.
authors.affiliation: Institute of Radioisotopes and Radiodiagnostic Products, NCSR Demokritos, 15310 Ag. Paraskevi, Athens, Greece. ipirme@rrp.demokritos.gr
authors.forename: I
authors.initials: I
authors.lastname: Pirmettis
authors.forename: Y
authors.initials: Y
authors.lastname: Arano
authors.forename: T
authors.initials: T
authors.lastname: Tsotakos
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: A
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: T
authors.initials: T
authors.lastname: Uehara
authors.forename: M
authors.initials: M
authors.lastname: Morais
authors.forename: J D G
authors.initials: JD
authors.lastname: Correia
authors.forename: I
authors.initials: I
authors.lastname: Santos
authors.forename: M
authors.initials: M
authors.lastname: Martins
authors.forename: S
authors.initials: S
authors.lastname: Pereira
authors.forename: C
authors.initials: C
authors.lastname: Triantis
authors.forename: P
authors.initials: P
authors.lastname: Kyprianidou
authors.forename: M
authors.initials: M
authors.lastname: Pelecanou
authors.forename: M
authors.initials: M
authors.lastname: Papadopoulos
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry*; D003911:Dextrans / Q000138:chemical synthesis* / Q000737:chemistry*; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism*; D008297:Male; D008358:Mannose / Q000737:chemistry*; D051379:Mice; D064847:Multimodal Imaging; D015609:Organotechnetium Compounds / Q000737:chemistry*; D049268:Positron-Emission Tomography; D021701:Sentinel Lymph Node Biopsy / Q000379:methods; D014057:Tomography, X-Ray Computed
chemical_list: D002614:Chelating Agents; D003911:Dextrans; D015609:Organotechnetium Compounds; D008358:Mannose