title: Gallium-68-labeled affibody molecule for PET imaging of PDGFRβ expression in vivo.
abstract: Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor involved, for example, in angiogenesis. Overexpression and excessive signaling of PDGFRβ has been observed in multiple malignant tumors and fibrotic diseases, making this receptor a pharmaceutical target for monoclonal antibodies and tyrosine kinase inhibitors. Successful targeted therapy requires identification of responding patients. Radionuclide molecular imaging would enable determination of the PDGFRβ status in all lesions using a single noninvasive repeatable procedure. Recently, we have demonstrated that the affibody molecule Z09591 labeled with (111)In can specifically target PDGFRβ-expressing tumors in vivo. The use of positron emission tomography (PET) as an imaging technique would provide superior resolution, sensitivity, and quantitation accuracy. In this study, a DOTA-conjugated Z09591 was labeled with the generator-produced positron emitting radionuclide (68)Ga (T1/2 = 67.6 min, Eβ + max = 1899 keV, 89% β(+)). (68)Ga-DOTA-Z09591 retained the capacity to specifically bind to PDGFRβ-expressing U-87 MG glioma cells. The half-maximum inhibition concentration (IC50) of (68)Ga-DOTA-Z09591 (6.6 ± 1.4 nM) was somewhat higher than that of (111)In-DOTA-Z09591 (1.4 ± 1.2 nM). (68)Ga-DOTA-Z09591 demonstrated specific (saturable) targeting of U-87 MG xenografts in immunodeficient mice. The tumor uptake at 2 h after injection was 3.7 ± 1.7% IA/g, which provided a tumor-to-blood ratio of 8.0 ± 3.1. The only organ with higher accumulation of radioactivity was the kidney. MicroPET imaging provided high-contrast imaging of U-87 MG xenografts. In conclusion, the (68)Ga-labeled affibody molecule Z09591 is a promising candidate for further development as a probe for imaging PDGFRβ expression in vivo using PET.
authors: Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University , Uppsala, Sweden.
authors: Joanna
authors: J
authors: Strand
authors: Zohreh
authors: Z
authors: Varasteh
authors: Olof
authors: O
authors: Eriksson
authors: Lars
authors: L
authors: Abrahmsen
authors: Anna
authors: A
authors: Orlova
authors: Vladimir
authors: V
authors: Tolmachev
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001932:Brain Neoplasms / Q000000981:diagnostic imaging; D045744:Cell Line, Tumor; D005260:Female; D005710:Gallium Radioisotopes / Q000737:chemistry; D005910:Glioma / Q000000981:diagnostic imaging; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007205:Indium Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D064847:Multimodal Imaging; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D049268:Positron-Emission Tomography; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry*; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: DPTA; PDGFR beta; PET; affibody molecule; gallium-68