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

Abstract

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.

Legumain-mediated self-assembly of a 131I-labelled agent for targeted radiotherapy of tumors

“…S18, ESI †). It was found that the Michaelis constant (K m ) of MAAN was 72.5 mM, which was lower than that of another legumain-responsive compound (K m = 266.29 mM) reported previously by our group, 33 indicating that MAAN possessed higher sensitivity toward legumain.…”

“…32 In our recent work, two legumain-targeted radiotracers were used for the noninvasive visualization of legumain in tumors via positron emission tomography (PET) imaging. 33 Given the high tumor specificity exhibited in animal models of these probes, legumain could be used as a potential target for cancer therapy. To our knowledge, TRT based on legumain has rarely been reported up to now.…”

Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer’s disease

“…Until the present work was accomplished, there were no AEP imaging studies reported in the field of neurodegenerative diseases. Previous imaging probes were primarily applied to tumors to explore the role of AEP in tumor progression and metastasis [ 42 , 43 ]. To the best of our knowledge, we here showed for the first time that up-regulated AEP in AD brain can be monitored by live-animal imaging analysis.…”

Development of a Promising 18F-Radiotracer for PET Imaging Legumain Activity In Vivo

“…So far, a large number of probes have been reported for the detection of legumain [ 6 , 11 , 13 , 19 , 20 , 21 , 22 , 23 , 24 ]. In 2015, Liang and co-workers reported a nuclear magnetic resonance (NMR) probe for imaging legumain in HEK293T tumor-bearing zebrafish [ 20 ].…”