We report a practical and high-yield synthesis of a bimodal bifunctional
ligand 3p-C-NETA-NCS containing the
isothiocyanate group for conjugation to a
tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a
tumor-targeting antibody,
trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to
trastuzumab conjugates of the known bifunctional
ligands C-
DOTA, C-
DTPA, and 3p-C-DEPA for radiolabeling kinetics with (90)Y and (177)Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with (90)Y and (177)Lu. (90)Y-3p-C-NETA-trastuzumab and (177)Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and
tumor targeting of (177)Lu-radiolabeled
trastuzumab conjugate using nude mice bearing ZR-75-1 human
breast cancer. (177)Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high
tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional
chelator that can be used for targeted RIT applications using (90)Y and (177)Lu and has the potential to replace
DOTA and
DTPA analogues in current clinical use.