Gallium-68-Labeled Affibody Molecule for PET Imaging of PDGFRβ Expression in Vivo

Platelet-derived growth factor receptor beta (PDGFR beta) is a transmembrane tyrosine kinase receptor involved, for example, in angiogenesis. Overexpression and excessive signaling of PDGFR beta 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 PDGFR beta 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 PDGFR beta-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 Ga-68 (T-1/2 = 67.6 min, E-beta + max = 1899 keV, 89% beta(+)). Ga-68-DOTA-Z09591 retained the capacity to specifically bind to PDGFR beta-expressing U-87 MG glioma cells. The half-maximum inhibition concentration (IC(5)0) of Ga-68-DOTA-Z09591 (6.6 +/- 1.4 nM) was somewhat higher than that of In-111-DOTA-Z09591 (1.4 +/- 1.2 nM). Ga-68-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 Ga-68-labeled affibody molecule Z09591 is a promising candidate for further development as a probe for imaging PDGFR beta expression in vivo using PET.