Gallium-68-labeled affibody molecule for PET imaging of PDGFRβ expression in vivo

J Strand, Z Varasteh, O Eriksson… - Molecular …, 2014 - ACS Publications
J Strand, Z Varasteh, O Eriksson, L Abrahmsen, A Orlova, V Tolmachev
Molecular pharmaceutics, 2014ACS Publications
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 …
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 111In 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 68Ga (T1/2 = 67.6 min, Eβ + max = 1899 keV, 89% β+). 68Ga-DOTA-Z09591 retained the capacity to specifically bind to PDGFRβ-expressing U-87 MG glioma cells. The half-maximum inhibition concentration (IC50) of 68Ga-DOTA-Z09591 (6.6 ± 1.4 nM) was somewhat higher than that of 111In-DOTA-Z09591 (1.4 ± 1.2 nM). 68Ga-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 68Ga-labeled affibody molecule Z09591 is a promising candidate for further development as a probe for imaging PDGFRβ expression in vivo using PET.
ACS Publications