title: Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu.
abstract: Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope ((90)Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin's lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides (90)Y and (177)Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with (90)Y and (177)Lu, and the corresponding (90)Y or (177)Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding (90)Y and (177)Lu, and the corresponding (90)Y- and (177)Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of (90)Y and (177)Lu.
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States. Electronic address: Chong@iit.edu.
authors: Hyun-Soon
authors: HS
authors: Chong
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States.
authors: Xiang
authors: X
authors: Sun
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States.
authors: Yunwei
authors: Y
authors: Chen
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States.
authors: Inseok
authors: I
authors: Sin
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States.
authors: Chi Soo
authors: CS
authors: Kang
authors: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States; Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States.
authors: Michael R
authors: MR
authors: Lewis
authors: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States.
authors: Dijie
authors: D
authors: Liu
authors: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States.
authors: Varyanna C
authors: VC
authors: Ruthengael
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States.
authors: Yongliang
authors: Y
authors: Zhong
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States.
authors: Ningjie
authors: N
authors: Wu
authors: Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States.
authors: Hyun A
authors: HA
authors: Song
mesh_terms: D000818:Animals; D008024:Ligands; D008187:Lutetium / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D011878:Radiotherapy; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D008024:Ligands; D015021:Yttrium Radioisotopes; D008187:Lutetium
keywords: Bifunctional ligands; Lu-177; Radioimmunotherapy; Y-90
references: Bioconjug Chem. 1991 Jan-Feb;2(1):26-31
references: 1908704
references: Bioorg Med Chem Lett. 2008 Nov 1;18(21):5792-5
references: 18845437
references: Nat Rev Drug Discov. 2004 Jun;3(6):488-99
references: 15173838
references: Bioconjug Chem. 2011 Jun 15;22(6):1128-35
references: 21604692
references: European J Org Chem. 2011 Nov 1;2011(33):6641-6648
references: 23794941
references: Nucl Med Biol. 2003 Aug;30(6):581-95
references: 12900284
references: Bioorg Med Chem Lett. 2008 Jun 1;18(11):3436-9
references: 18445528
references: Semin Nucl Med. 2001 Oct;31(4):330-41
references: 11710775
references: Q J Nucl Med Mol Imaging. 2008 Jun;52(2):166-73
references: 18043537
references: Bioconjug Chem. 2012 Sep 19;23(9):1775-82
references: 22881720
references: Crit Rev Oncol Hematol. 2001 Jul-Aug;39(1-2):181-94
references: 11418315
references: Semin Radiat Oncol. 2000 Apr;10(2):73-93
references: 10727597
references: Chem Commun (Camb). 2011 May 21;47(19):5584-6
references: 21468393