title: Comparison of benzoate- and dodecaborate-based linkers for attachment of radioiodine to HER2-targeting Affibody ligand.
abstract: The use of radionuclide molecular imaging enables the selection of patients for treatment using molecular medicine. Preclinical studies have demonstrated that a novel low-molecular-weight affinity ligand, Affibody molecule Z(HER2:342) can image the expression of HER2 with high sensitivity and specificity in tumour xenografts and has a potential for the selection of patients for treatment using Herceptin or other anti-HER2 medicine. In this study, we performed a comparative evaluation of two possible linkers for radioiodination of the Affibody molecule Z(HER2:342), 4-iodobenzoate (PIB) and [4-isothiocyanatobenzyl)-amino]-undecahydro-closo-dodecaborate (DABI). It was shown that the use of DABI makes it possible to obtain radioiodinated Z(HER2:342) with preserved capacity for selective binding to HER2-expressing cells. There was no difference between 125I-PIB-Z(HER2:342) and 125I-DABI-Z(HER2:342) in cellular retention of radioactivity after interrupted incubation with radiolabelled Affibody ligands. In vivo, the biodistribution of 125I-PIB-Z(HER2:342) was characterized by a high tumour uptake at 4 h pi (12.7+/-4.6% IA/g) and a quick clearance from blood and normal organs. The tumour uptake of 125I-DABI-Z(HER2:342) was appreciably lower (2.7+/-1.2% IA/g), and a high uptake of this conjugate in the liver was observed. A gamma-camera experiment (at 6 h pi) demonstrated that the use of 125I-PIB-Z(HER2:342) provided a much better contrast of imaging HER2-expressing xenografts than the use of 125I-DABI-Z(HER2:342). In conclusion, 125I-PIB-Z(HER2:342) is superior to 125I-DABI-Z(HER2:342) as an agent for imaging HER2 expression in vivo.
authors.affiliation: Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.
authors.forename: Thuy
authors.initials: T
authors.lastname: Tran
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.forename: Igor
authors.initials: I
authors.lastname: Sivaev
authors.forename: Mattias
authors.initials: M
authors.lastname: Sandström
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000345:Affinity Labels; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001682:Biological Availability; D001896:Boron Compounds / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011877:Radionuclide Imaging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D051598:Whole Body Imaging; D023041:Xenograft Model Antitumor Assays
chemical_list: D000345:Affinity Labels; D001565:Benzoates; D001896:Boron Compounds; D007457:Iodine Radioisotopes; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; C119788:dodecaborate