TY - JOUR
T1 - Quantitative PET Imaging of Tissue Factor Expression Using 18F-labled Active Site Inhibited Factor VII
AU - Nielsen, Carsten H
AU - Erlandsson, Maria
AU - Jeppesen, Troels E
AU - Jensen, Mette M
AU - Kristensen, Lotte K
AU - Madsen, Jacob
AU - Petersen, Lars C
AU - Kjaer, Andreas
N1 - Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an 18F-labeled derivative of factor VII. Methods: Active site-inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-18F-fluorobenzoate and purified. The corresponding product, 18F-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 h 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 enzyme-linked immunosorbent assay and correlated with the uptake of 18F-FVIIai in the tumors measured in vivo by PET imaging. Results: The PET images showed high uptake of 18F-FVIIai in the tumor regions, with a mean uptake of 2.5 ± 0.3 percentage injected dose per gram (%ID/g) (mean ± SEM) 4 h after injection of 7.3-9.3 MBq of 18F-FVIIai and with an average maximum uptake in the tumors of 7.1 ± 0.7%ID/g at 4 h. In comparison, the muscle uptake was 0.2 ± 0.01 %ID/g at 4 h. At 4 h, the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of 18F-FVIIai from 2.9 ± 0.1 to 1.4 ± 0.1 %ID/g (P , 0.001). The uptake of 18F-FVIIai measured in vivo by PET imaging correlated (r 5 0.72, P , 0.02) with TF protein level measured ex vivo. Conclusion: 18F-FVIIai is a promising PET tracer for specific and noninvasive 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.
AB - Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an 18F-labeled derivative of factor VII. Methods: Active site-inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-18F-fluorobenzoate and purified. The corresponding product, 18F-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 h 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 enzyme-linked immunosorbent assay and correlated with the uptake of 18F-FVIIai in the tumors measured in vivo by PET imaging. Results: The PET images showed high uptake of 18F-FVIIai in the tumor regions, with a mean uptake of 2.5 ± 0.3 percentage injected dose per gram (%ID/g) (mean ± SEM) 4 h after injection of 7.3-9.3 MBq of 18F-FVIIai and with an average maximum uptake in the tumors of 7.1 ± 0.7%ID/g at 4 h. In comparison, the muscle uptake was 0.2 ± 0.01 %ID/g at 4 h. At 4 h, the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of 18F-FVIIai from 2.9 ± 0.1 to 1.4 ± 0.1 %ID/g (P , 0.001). The uptake of 18F-FVIIai measured in vivo by PET imaging correlated (r 5 0.72, P , 0.02) with TF protein level measured ex vivo. Conclusion: 18F-FVIIai is a promising PET tracer for specific and noninvasive 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.
U2 - 10.2967/jnumed.115.154849
DO - 10.2967/jnumed.115.154849
M3 - Journal article
C2 - 26383146
SN - 0161-5505
VL - 57
SP - 89
EP - 95
JO - The Journal of Nuclear Medicine
JF - The Journal of Nuclear Medicine
IS - 1
ER -