title: Synthesis and preclinical evaluation of bifunctional ligands for improved chelation chemistry of 90Y and 177Lu for targeted radioimmunotherapy.
abstract: 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.
authors.affiliation: Chemistry Division, Biological and Chemical Sciences Department, Illinois Institute of Technology, Chicago, Illinois 60616, USA.
authors.forename: Chi Soo
authors.initials: CS
authors.lastname: Kang
authors.forename: Xiang
authors.initials: X
authors.lastname: Sun
authors.forename: Fang
authors.initials: F
authors.lastname: Jia
authors.forename: Hyun A
authors.initials: HA
authors.lastname: Song
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Lewis
authors.forename: Hyun-Soon
authors.initials: HS
authors.lastname: Chong
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D007700:Kinetics; D008024:Ligands; D008187:Lutetium / Q000737:chemistry*; D016499:Radioimmunotherapy; D000068878:Trastuzumab; D015021:Yttrium Radioisotopes / Q000737:chemistry*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002614:Chelating Agents; D008024:Ligands; D015021:Yttrium Radioisotopes; D008187:Lutetium; D000068878:Trastuzumab