Radiofluorinated Smart Probes for Noninvasive PET Imaging of Legumain Activity in Living Subjects

• Published in: Analytical chemistry (Washington) Vol. 92; no. 17; pp. 11627 - 11634
• Main Authors: Qiu, Ling, Li, Xi, Lv, Gaochao, Seimbille, Yann, Li, Ke, Peng, Ying, Liu, Qingzhu, Xie, Minhao, Lin, Jianguo
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.09.2020
• Subjects: Analytical chemistry; Animals; Biosensing Techniques; Cell Membrane Permeability; Chemistry; Coinjection; Contrast Media - chemistry; Cysteine Endopeptidases - metabolism; early diagnosis; Female; Fluorine isotopes; Fluorine Radioisotopes - chemistry; Glutamic Acid - chemistry; HCT116 Cells; Histidine; Histidine - chemistry; Humans; Imaging techniques; Injection; Isotope Labeling; Legumain; liver; Male; Medical imaging; Metastases; metastasis; Mice; Mice, Nude; Molecular Structure; neoplasms; Neoplasms, Experimental; Peptides - chemistry; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; prediction; Probes; Radiochemistry; Radiopharmaceuticals; Sensitivity and Specificity; Tomography; Tumors
• ISSN: 0003-2700; 1520-6882; 1520-6882
• DOI: 10.1021/acs.analchem.0c01253

Overexpression of legumain is closely associated with tumor proliferation, invasion, and metastasis. Because of its intrinsic properties, such as high sensitivity and resolution, positron emission tomography (PET) has become an effective imaging technique for early diagnosis, treatment response prediction, and monitoring. Herein, two legumain-targeting radiofluorinated smart probes ( 18 F-2 and 18 F-3) as well as a control probe ( 18 F-1) were specifically designed for PET imaging of legumain activity in tumors. 18 F-1, 18 F-2, and 18 F-3 were obtained with high radiochemical yield (RCY > 60%) and radiochemical purity (RCP > 99%) using a convenient “one-step” 18F-labeling method. The probes 18 F-2 and 18 F-3 exhibited high response to legumain activity and reductive environment and revealed comparable uptake in HCT116 cells (4.22% ± 0.14% and 4.64% ± 0.32% for 18 F-2 and 18 F-3, respectively; 8.46% ± 0.33% and 9.05% ± 0.24% for co-treatment of 18 F-2 + 2 and 18 F-3 + 3 at 1 h), while the control probe 18 F-1 showed no response. PET imaging of tumor-bearing mice showed that the co-injection strategy ( 18 F-2 + 2 and 18 F-3 + 3) resulted in higher tumor uptake (3.57% ± 0.37% and 3.72% ± 0.19% ID/g at 10 min, respectively) than the single injection strategy (2.59% ± 0.19% and 2.60% ± 0.46% ID/g for 18 F-2 and 18 F-3, respectively). In addition, introduction of the trimeric histidine-glutamate (HEHEHE) tag to 18 F-3 reduced the liver uptake by almost two-fold without any noticeable effect on the tumor uptake. All the results indicate that 18 F-3 holds great potential applications in clinics for sensitive and specific PET imaging of legumain activity in tumors.