Design and Development of ^99mTc-‘4+1’-Labeled Dextran-Mannose Derivatives as Potential Radiopharmaceuticals for Sentinel Lymph Node Detection

Abstract

The synthesis, labeling, and biological evaluation of a dextran derivative (DCM-30-iso) as potential radiopharmaceutical for sentinel lymph node imaging is presented. DCM-30-iso bears mannose as active moiety and isocyanide as ligand for technetium through the formation of a '4+1' Tc(III) mixed-ligand complex. A second derivative without mannose (DC-25-iso) was also prepared and evaluated as control. DCM-30-iso and DC-25-iso were synthesized from dextran in four steps (>50% overall yield) and characterized by spectroscopic methods. Labeling with (99m)Tc was achieved by reaction with 2,2',2''-nitrilotris(ethanethiol) and (99m)Tc-EDTA. Radiochemical purity was above 90% and was stable for at least 4 hours postlabeling at 37°C. The identity of the (99m)Tc complex was established through comparative HPLC studies using the well-characterized analogous Re-DC-25-iso complex. Biodistribution and imaging experiments of (99m)Tc-DCM-30-iso showed high uptake in the popliteal lymph node, which could be blocked with preinjection of mannose, and very low uptake in other nodes and organs. The nonmannosylated (99m)Tc-DC-25-iso derivative showed negligible uptake in all lymph nodes. The novel dextran-mannose derivative DCM-30-iso can be successfully labeled with (99m)Tc to give a well-characterized '4+1' complex with favorable biological properties as sentinel lymph node imaging agent.

Design and Synthesis of 99mTcN-Labeled Dextran-Mannose Derivatives for Sentinel Lymph Node Detection

“…Recently, aiming to provide more stable and chemically well-defined target-specific 99m Tc complexes for SLND, 99m Tc-tricarbonyl technology has been applied to label mannosylated-dextran conjugates in combination with pyrazolyldiamine chelator that selectively react with the fac -[ 99m Tc(CO) 3 (H 2 O) 3 ] + metal fragment [ 11 ]. According to the mannosylated-dextran conjugates strategy, ‘4 + 1’ mannosylated-dextran Tc(III) mixed-ligand complexes have been also reported [ 17 ].…”