title: Position for site-specific attachment of a DOTA chelator to synthetic affibody molecules has a different influence on the targeting properties of 68Ga- compared to 111in-labeled conjugates.
abstract: Affibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1, which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes.
authors.forename: Hadis
authors.initials: H
authors.lastname: Honarvar
authors.forename: Joanna
authors.initials: J
authors.lastname: Strand
authors.forename: Anna
authors.initials: A
authors.lastname: Perols
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.forename: Ram Kumar
authors.initials: RK
authors.lastname: Selvaraju
authors.forename: Amelie
authors.initials: A
authors.lastname: Eriksson Karlström
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D005260:Female; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D007553:Isotope Labeling; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis*
chemical_list: D002614:Chelating Agents; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D011993:Recombinant Fusion Proteins; C000595852:affibody Z(HER2-S1); C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid