title: Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using(90)Y or(177)Lu.
abstract: BACKGROUND
  Therapeutic potential of β-emitting cytotoxic radionuclides (90)Y and (177)Lu has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy (90)Y and (177)Lu. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin αvβ3 protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of (90)Y and (177)Lu.
  
  
  METHODS
  5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-C-NETA-c(RGDyK). (177)Lu-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice.
  
  
  RESULTS
  The new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, (90)Y or (177)Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (>99%, RT, <1 min). (90)Y- and (177)Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with (90)Y or (177)Lu. (177)Lu-radiolabeled 5p-C-NETA-c(RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile.
  
  
  CONCLUSIONS
  The results of in vitro and in vivo evaluation suggest that 5p-C-NETA is an effective bifunctional chelate of (90)Y and (177)Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals.
authors.affiliation: Chemistry Division, Biological and Chemical Sciences Department, Illinois Institute of Technology, Chicago, IL.
authors.forename: Chi Soo
authors.initials: CS
authors.lastname: Kang
authors.affiliation: Chemistry Division, Biological and Chemical Sciences Department, Illinois Institute of Technology, Chicago, IL.
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Chemistry Division, Biological and Chemical Sciences Department, Illinois Institute of Technology, Chicago, IL.
authors.forename: Hyunbeom
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO.
authors.forename: Dijie
authors.initials: D
authors.lastname: Liu
authors.affiliation: Chemistry Division, Biological and Chemical Sciences Department, Illinois Institute of Technology, Chicago, IL.
authors.forename: Xiang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Chemistry Division, Biological and Chemical Sciences Department, Illinois Institute of Technology, Chicago, IL.
authors.forename: Junghun
authors.initials: J
authors.lastname: Kweon
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital; Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lewis
authors.affiliation: Chemistry Division, Biological and Chemical Sciences Department, Illinois Institute of Technology, Chicago, IL. Electronic address: Chong@iit.edu.
authors.forename: Hyun-Soon
authors.initials: HS
authors.lastname: Chong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D005909:Glioblastoma / Q000473:pathology / Q000532:radiotherapy; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D007553:Isotope Labeling; D007700:Kinetics; D008187:Lutetium / Q000627:therapeutic use*; D051379:Mice; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: C529856:(2-(4,7-biscarboxymethyl(1,4,7)triazacyclonona-1-yl-ethyl)carbonylmethylamino)acetic acid; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D009842:Oligopeptides; D015021:Yttrium Radioisotopes; D008187:Lutetium; C047981:arginyl-glycyl-aspartic acid
keywords: Bifunctional chelate; Cyclic RGD peptide; Lu-177; Targeted radiotherapy; Y-90