TY - JOUR
T1 - Oxime Coupling of Active Site Inhibited Factor Seven with a Nonvolatile, Water-Soluble Fluorine-18 Labeled Aldehyde
AU - Jeppesen, Troels E.
AU - Kristensen, Lotte K.
AU - Nielsen, Carsten H
AU - Petersen, Lars C.
AU - Kristensen, Jesper B
AU - Behrens, Carsten
AU - Madsen, Jacob
AU - Kjaer, Andreas
PY - 2019/3/20
Y1 - 2019/3/20
N2 - A nonvolatile fluorine-18 aldehyde prosthetic group was developed from [18F]SFB, and used for site-specific labeling of active site inhibited factor VII (FVIIai). FVIIai has a high affinity for tissue factor (TF), a transmembrane protein involved in angiogenesis, proliferation, cell migration, and survival of cancer cells. A hydroxylamine N-glycan modified FVIIai (FVIIai-ONH2) was used for oxime coupling with the aldehyde [18F]2 under mild and optimized conditions in an isolated RCY of 4.7 ± 0.9%, and a synthesis time of 267 ± 5 min (from EOB). Retained binding and specificity of the resulting [18F]FVIIai to TF was shown in vitro. TF-expression imaging capability was evaluated by in vivo PET/CT imaging in a pancreatic human xenograft cancer mouse model. The conjugate showed exceptional stability in plasma (>95% at 4 h) and a binding fraction of 90%. In vivo PET/CT imaging showed a mean tumor uptake of 3.8 ± 0.2% ID/g at 4 h post-injection, a comparable uptake in liver and kidneys, and low uptake in normal tissues. In conclusion, FVIIai was labeled with fluorine-18 at the N-glycan chain without affecting TF binding. In vitro specificity and a good in vivo imaging contrast at 4 h postinjection was demonstrated.
AB - A nonvolatile fluorine-18 aldehyde prosthetic group was developed from [18F]SFB, and used for site-specific labeling of active site inhibited factor VII (FVIIai). FVIIai has a high affinity for tissue factor (TF), a transmembrane protein involved in angiogenesis, proliferation, cell migration, and survival of cancer cells. A hydroxylamine N-glycan modified FVIIai (FVIIai-ONH2) was used for oxime coupling with the aldehyde [18F]2 under mild and optimized conditions in an isolated RCY of 4.7 ± 0.9%, and a synthesis time of 267 ± 5 min (from EOB). Retained binding and specificity of the resulting [18F]FVIIai to TF was shown in vitro. TF-expression imaging capability was evaluated by in vivo PET/CT imaging in a pancreatic human xenograft cancer mouse model. The conjugate showed exceptional stability in plasma (>95% at 4 h) and a binding fraction of 90%. In vivo PET/CT imaging showed a mean tumor uptake of 3.8 ± 0.2% ID/g at 4 h post-injection, a comparable uptake in liver and kidneys, and low uptake in normal tissues. In conclusion, FVIIai was labeled with fluorine-18 at the N-glycan chain without affecting TF binding. In vitro specificity and a good in vivo imaging contrast at 4 h postinjection was demonstrated.
U2 - 10.1021/acs.bioconjchem.8b00900
DO - 10.1021/acs.bioconjchem.8b00900
M3 - Journal article
C2 - 30676028
SN - 1043-1802
VL - 30
SP - 775
EP - 784
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 3
ER -
