Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 4/2020

01-08-2020 | Computed Tomography | Research Article

Targeting Phosphatidylethanolamine with Fluorine-18 Labeled Small Molecule Probe for Apoptosis Imaging

Authors: Gongjun Yuan, Shaoyu Liu, Hui Ma, Shu Su, Fuhua Wen, Xiaolan Tang, Zhanwen Zhang, Jing Zhao, Liping Lin, Xianhong Xiang, Dahong Nie, Ganghua Tang

Published in: Molecular Imaging and Biology | Issue 4/2020

Login to get access

Abstract

Purpose

Externalization of phosphatidylethanolamine (PE) in dying cells makes the phospholipid an attractive target for apoptosis imaging. However, no ideal PE-targeted positron emission tomography (PET) radiotracer was developed. The goal of the study was to develop a novel PE-targeted radiopharmaceutical to imaging apoptosis.

Procedure

In this study, we have radiolabeled PE-binding polypeptide duramycin with fluorine-18 for PET imaging of apoptosis. Al[18F]F-NOTA-PEG3-duramycin was synthesized via chelation reaction of NOTA-PEG3-duramycin with Al[18F]F. PE-binding capacity of Al[18F]F-NOTA-PEG3-duramycin was determined in a competitive radiometric PE-binding assay. The pharmacokinetic profile was evaluated in Kunming mice. The apoptosis imaging capacity of Al[18F]F-NOTA-PEG3-duramycin was evaluated using in vitro cell uptake assay with camptothecin-treated Jurkat cells, along with in vivo PET imaging using erlotinib-treated nude mice.

Results

The total synthesis procedure lasted for 30 min, with a decay-uncorrected radiochemical yield of 21.3 ± 2.6 % (n = 10). Compared with the control cells, the binding of Al[18F]F-NOTA-PEG3-duramycin with camptothecin-induced apoptotic cells resulted in a tripling increase. A competitive radiometric PE-binding assay strongly confirmed the binding of Al[18F]F-NOTA-PEG3-duramycin to PE. The biodistribution study showed rapid blood clearance, prominent kidney retention, and low liver uptake. In the in vivo PET/CT imaging, Al[18F]F-NOTA-PEG3-duramycin demonstrated 2-fold increase in erlotinib-treated HCC827 tumors in nude mice.

Conclusion

Considering the facile preparation and improved biological properties, Al[18F]F-NOTA-PEG3-duramycin seems to be a promising PET tracer candidate for imaging apoptosis in the monitoring of cancer treatment.
Appendix
Available only for authorised users
Literature
1.
Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629CrossRef
2.
Meiler J, Schuler M (2006) Therapeutic targeting of apoptotic pathways in cancer. Curr Drug Targets 7:1361–1369CrossRef
3.
Allen AM, Ben-Ami M, Reshef A et al (2012) Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with 18F-ML-10. Eur J Nucl Med Mol Imaging 39:1400–1408CrossRef
4.
Blankenberg FG, Kalinyak J, Liu L et al (2006) 99mTc-HYNIC-Annexin V SPECT imaging of acute stroke and its response to neuroprotective therapy with anti Fas ligand antibody. Eur J Nucl Med Mol Imaging 33:566–574CrossRef
5.
Kartachova M, van Zandwijk N, Burgers S et al (2007) Prognostic significance of 99mTc-Hynic-rh-Annexin V scintigraphy during platinum based chemotherapy in advanced lung cancer. J Clin Oncol 25:2534–2539CrossRef
6.
Oborski MJ, Laymon CM, Lieberman FS et al (2014) First use of 18F-labeled ML-10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy. Brain Behav 4:312–315CrossRef
7.
Zeng W, Wang X, Xu P, Liu G, Eden HS, Chen X (2015) Molecular imaging of apoptosis: from micro to macro. Theranostics 5:559–582CrossRef
8.
Challapalli A, Kenny LM, Hallett WA et al (2013) 18F-ICMT-11, a caspase-3-specific PET tracer for apoptosis: biodistribution and radiation dosimetry. J Nucl Med 54:1551–1556CrossRef
9.
Dubash SR, Merchant S, Heinzmann K et al (2018) Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induce caspase 3/7 activation in breast and lung cancer. Eur J Nucl Med Mol Imaging 45:2285–2299CrossRef
10.
Zhao M (2011) Lantibiotics as probes for phosphatidylethanolamine. Amino Acids 41:1071–1079CrossRef
11.
Johnson SE, Li Z, Liu Y et al (2013) Whole-body imaging of high-dose ionizing irradiation induced tissue injuries using 99m Tc-duramycin. J Nucl Med 54:1397–1403CrossRef
12.
Elvas F, Vangestel C, Pak K, Vermeulen P, Gray B, Stroobants S, Staelens S, Wyffels L (2016) Early prediction of tumor response to treatment: preclinical validation of 99mTc-duramycin. J Nucl Med 57:805–811CrossRef
13.
Liu Z, Larsen BT, Lerman LO, Gray BD, Barber C, Hedayat AF, Zhao M, Furenlid LR, Pak KY, Woolfenden JM (2016) Detection of atherosclerotic plaques in ApoE-deficient mice using 99mTc-duramycin. Nucl Med Biol 43:496–505CrossRef
14.
Audi SH, Jacobs ER, Zhang X et al (2017) Protection by inhaled hydrogen therapy in a rat model of acute lung injury can be tracked in vivo using molecular imaging. Shock 48(4):467–476CrossRef
15.
Medhora M, Haworth S, Liu Y et al (2016) Biomarkers for radiation pneumonitis using noninvasive molecular imaging. J Nucl Med 57:1296–1301CrossRef
16.
Li Y, Liu C, Xu X, Lu X, Luo J, Gray B, Pak KY, Cheng J, Zhang Y (2018) [99mTc]duramycin, a potential molecular probe for early prediction of tumor response after chemotherapy. Nucl Med Biol 66:18–25CrossRef
17.
Zhao M, Li Z (2012) A single-step kit formulation for the 99mTc-labeling of HYNIC-duramycin. Nucl Med Biol 39:1006–1011CrossRef
18.
Wang L, Wang F, Fang W et al (2015) The feasibility of imaging myocardial ischemic/reperfusion injury using 99mTc-labeled duramycin in a porcine model. Nucl Med Biol 42:198–204CrossRef
19.
Yao S, Hu K, Tang G et al (2015) Positron emission tomography imaging of cell death with [18F]FPDuramycin. Apoptosis 19:841–850CrossRef
20.
McBride WJ, Sharkey RM, Karacay H et al (2009) A novel method of 18F radiolabeling for PET. J Nucl Med 50:991–998CrossRef
21.
Luan X, Huang Y, Gao S, Sun X, Wang S, Ma L, Teng X, Lu H, Yu J, Yuan S (2016) 18F-alfatide PET/CT may predict short-term outcome of concurrent chemoradiotherapy in patients with advanced non-small cell lung cancer. Eur J Nucl Med Mol Imaging 43:2336–2342CrossRef
22.
Wu J, Wang S, Zhang X et al (2018) 18F-Alfatide II PET/CT for identification of breast cancer: a preliminary clinical study. J Nucl Med 59:1809–1816CrossRef
23.
24.
Lieberman BP, Ploessl K, Wang L et al (2011) PET imaging of glutaminolysis in tumors by 18F-(2S, 4R)4-fluoroglutamine. J Nucl Med 52:1947–1955CrossRef
25.
Perreault A, Richter S, Bergman C et al (2016) Targeting phosphatidylserine with a 64Cu-labeled peptide for molecular imaging of apoptosis. Mol Pharm 13:3564–3577CrossRef
26.
Zhao M, Li Z, Bugenhagen S (2008) 99mTc-labeled duramycin as a novel phosphatidylethanolamine-binding molecular probe. J Nucl Med 49:1345–1352CrossRef
27.
28.
29.
Bernard-Gauthier V, Lepage ML, Waengler B, Bailey JJ, Liang SH, Perrin DM, Vasdev N, Schirrmacher R (2018) Recent advances in 18F radiochemistry: a focus on B - 18F, Si - 18F, Al -18F, and C - 18F radiofluorination via spirocyclic iodonium ylides. J Nucl Med 59:568–572CrossRef
30.
Palmieri L, Elvas F, Vangestel C et al (2018) [99mTc]duramycin for cell death imaging: impact of kit formulation, purification and species difference. Nucl Med Biol 56:1–9CrossRef
31.
Elvas F, Vangestel C, Rapic S, Verhaeghe J, Gray B, Pak K, Stroobants S, Staelens S, Wyffels L (2015) Characterization of [99mTc]duramycin as a SPECT imaging agent for early assessment of tumor apoptosis. Mol Imaging Biol 17:838–847CrossRef
32.
Da Pieve C, Allot L, Martins CD et al (2016) Efficient 18F-AlF radiolabeling of ZHER3:8683 affibody molecule for imaging of HER3 positive tumors. Bioconjug Chem 27:1839–1849CrossRef
33.
González Trotter DE, Meng X, McQuade P, Rubins D, Klimas M, Zeng Z, Connolly BM, Miller PJ, O'Malley SS, Lin SA, Getty KL, Fayadat-Dilman L, Liang L, Wahlberg E, Widmark O, Ekblad C, Frejd FY, Hostetler ED, Evelhoch JL (2017) In vivo imaging of the programmed death ligand 1 by 18F PET. J Nucl Med 58(11):1852–1857CrossRef
34.
Piotrowska Z, Sequist LV (2016) Treatment of EGFR-mutant lung cancers after progression in patients receiving first-line EGFR tyrosine kinase inhibitors: a review. JAMA Oncol 2:948–954CrossRef
35.
Rosell R, Carcereny E, Gervais R et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial. Lancet Oncol 13:239–246CrossRef
36.
Zhou C, Wu YL, Chen G et al (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742CrossRef
37.
Hu S, Kiesewetter DO, Zhu L, Guo N, Gao H, Liu G, Hida N, Lang L, Niu G, Chen X (2012) Longitudinal PET imaging of doxorubicin-induced cell death with 18F-Annexin V. Mol Imaging Biol 14:762–770CrossRef
38.
Wang MW, Wang F, Zheng YJ, Zhang YJ, Zhang YP, Zhao Q, Shen CK, Wang Y, Sun SH (2013) An in vivo molecular imaging probe (18)F-Annexin B1 for apoptosis detection by PET/CT: preparation and preliminary evaluation. Apoptosis 18:238–247CrossRef
39.
Belhocine T, Steinmetz N, Hustinx R et al (2002) Increase uptake of the apoptosis-imaging agent 99mTc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res 8(9):2766–2774PubMed
40.
Mandl SJ, Man C, Edinger M et al (2004) Multi-modality imaging identifies key times for annexin V imaging as an early predictor of therapeutic outcome. Mol Imaging 3(1):1–8CrossRef
41.
Vance JE (2008) Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res 49:1377–1387CrossRef
Metadata
Title
Targeting Phosphatidylethanolamine with Fluorine-18 Labeled Small Molecule Probe for Apoptosis Imaging
Authors
Gongjun Yuan
Shaoyu Liu
Hui Ma
Shu Su
Fuhua Wen
Xiaolan Tang
Zhanwen Zhang
Jing Zhao
Liping Lin
Xianhong Xiang
Dahong Nie
Ganghua Tang
Publication date
01-08-2020
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 4/2020
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-019-01460-0

Other articles of this Issue 4/2020

Molecular Imaging and Biology 4/2020 Go to the issue

Research Article

Multimodal Imaging Techniques Show Differences in Homing Capacity Between Mesenchymal Stromal Cells and Macrophages in Mouse Renal Injury Models

Brief Article

Type of Anaesthetic Influences [11C]MDL100,907 Binding to 5HT2A Receptors in Porcine Brain

Research Article

Integrin α6-Targeted Magnetic Resonance Imaging of Hepatocellular Carcinoma in Mice

Research Article

Next-Generation Radiogenomics Sequencing for Prediction of EGFR and KRAS Mutation Status in NSCLC Patients Using Multimodal Imaging and Machine Learning Algorithms

Review Article

Quantum Dot-Based Simultaneous Multicolor Imaging

Research Article

[99mTc]MIBI SPECT/CT for Identifying Dystonic Muscles in Patients with Primary Cervical Dystonia