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Quantitative PET Imaging of Tissue Factor Expression Using 18F-labled Active Site Inhibited Factor VII

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Tissue factor (TF) is up regulated in many solid tumors and its expression is linked to tumor angiogenesis, invasion, metastasis and prognosis. A non-invasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII (FVII) is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an (18)F-labeled derivative of FVII.

METHODS: Active site inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-[(18)F]-fluorobenzoate ([(18)F]SFB) and purified. The corresponding product, [(18)F]FVIIai, was injected into nude mice with subcutaneous human pancreatic xenograft tumors (BxPC-3) and investigated using small animal PET/CT imaging 1, 2 and 4 hours after injection. Ex vivo biodistribution was performed after the last imaging session, and tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by ELISA and correlated with the uptake of [(18)F]FVIIai in the tumors measured in vivo by PET imaging.

RESULTS: The PET images showed high uptake of [(18)F]FVIIai in the tumor regions with a mean uptake of 2.54 ± 0.27 %ID/g (Mean ± SEM) 4 hours after injection of 7.29-9.29 MBq [(18)F]FVIIai and with an average maximum uptake in the tumors of 7.08 ± 0.72 %ID/g at 4 hours. In comparison, the muscle uptake was 0.19 ± 0.01 %ID/g at 4 hours. At 4 hours the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of [(18)F]FVIIai from 2.93 ± 0.08 to 1.37 ± 0.06 %ID/g (p<0.001). The uptake of [(18)F]FVIIai measured in vivo by PET imaging correlated (r=0.72, p<0.02) with TF protein level measured ex vivo.

CONCLUSION: [(18)F]FVIIai is a promising PET tracer for specific and non-invasive imaging of tumor TF expression. The tracer merits further development and clinical translation, with potential to become a companion diagnostics for emerging TF targeted therapies.

OriginalsprogEngelsk
TidsskriftThe Journal of Nuclear Medicine
Vol/bind57
Udgave nummer1
Sider (fra-til)89-95
Antal sider7
ISSN0161-5505
DOI
StatusUdgivet - 1 jan. 2016

ID: 147663148