Synthesis and Evaluation of [ 18 F]AlF-NOTA-c- D VAP: A Novel PET Probe for Imaging GRP78 in Cancer

作者：Jiawen Huang, Lu Bai, Dazhi Shi, Wenhao Jiang, Pan Chen, Dong Ye, Xiaojun Zhang, Jiangling Peng, Jinqiang Hou, Yu‐Jing Lu, Xiaohong Huang, Ganghua Tang, Shun Huang · 发表于：Molecular Pharmaceutics · 年份：2024 · DOI：10.1021/acs.molpharmaceut.3c01228 · 被引用次数：4 · 研究领域：Heat shock proteins research、Endoplasmic Reticulum Stress and Disease、Protein Structure and Dynamics

GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [ 18 F]AlF-NOTA-c- D VAP, for targeted tumor imaging of GRP78. [ 18 F]AlF-NOTA-c- D VAP was radiolabeled with fluoride-18 using the aluminum-[ 18 F]fluoride ([ 18 F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [ 18 F]AlF-NOTA-c- D VAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe’s performance. Docking studies and pharmacokinetic analyses of [ 18 F]AlF-NOTA-c- D VAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe’s binding affinity to GRP78 was analyzed by molecular docking simulation. [ 18 F]AlF-NOTA-c- D VAP was radiolabeled in just 25 min with a high yield of 51 ± 16%...