Transbilayer phospholipids molecular imaging
© Belhocine and Prato; licensee Springer. 2011
Received: 20 May 2011
Accepted: 22 August 2011
Published: 22 August 2011
Nuclear medicine has become a key part of molecular imaging. In the present review article, we focus on the transbilayer phospholipids as exquisite targets for radiolabelled probes in molecular imaging. Asymmetry of phospholipid distribution is a characteristic of mammalian cell membranes. Phosphatidylcholine and sphyngomyelin cholinophospholipids are primarily located within the external leaflet of the cell membrane. Phosphatidylserine and phosphatidylethanolamine aminophospholipids, and also phosphatidylinositol are primarily located within the internal leaflet of the cell membrane. New radiolabelled tracers have been designed in preclinical and clinical research for PET-CT and SPECT-CT molecular imaging of transbilayer phospholipids.
Keywordsphospholipids molecular imaging PET-CT SPECT-CT
In this beginning of the twenty-first century, personalized molecular medicine is the objective of molecular diagnosis, molecular imaging, and molecular therapy [1, 2]. Molecular imaging (MI) includes a number of morphological imaging techniques (i.e. ultrasound, computed tomography and magnetic resonance imaging), and optical imaging techniques (i.e. bioluminescence and fluorescence imaging) [3, 4]. In addition, nuclear medicine with radiolabelled probes has become a key part of MI, especially with 18F-fluorodeoxyglucose (18F-FDG) metabolic imaging . New radiolabelled tracers have been designed for positron emission tomography-computed tomography (PET-CT) and single-photon emission computed tomography-computed tomography (SPECT-CT) molecular imaging . In this review article, we focus on the transbilayer phospholipids as exquisite targets for radiolabelled probes in molecular imaging.
There is no universally accepted definition of molecular imaging [5, 7]. In 2000, the Society of Molecular Imaging http://www.molecularimaging.org/ defined molecular imaging as: 'the characterization and measurement of biological processes in living animals at the cellular and molecular level'. In 2005, the European Society for Molecular Imaging http://www.e-smi.eu formulated a definition of molecular imaging as: 'the characterisation of the dynamics of the molecular processes in the living organisms in vivo. In vivo molecular imaging is a science combining molecular biology, cellular biology and physiology with imaging in living subjects'. In 2006, the Federation of Asian Societies for Molecular Imaging (FASMI: http://fasmi.org/) defined molecular imaging as: ' the characterization and measurement of biological processes in living animals at the cellular and molecular level by means of non-invasive (or minimally invasive) imaging'. In 2007, the Society of Nuclear Medicine Molecular Imaging Center of Excellence http://interactive.snm.org/ definitions task force approved this definition of molecular imaging as: 'the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems' . A MI probe is a molecule used in molecular imaging to deliver a tracer to a specific organ or tissue. A probe typically consists of a ligand containing or linked to a signalling label. The label provides the signal (i.e. electromagnetic wave, light and radiation) that can be picked up by a detector, and the ligand carries the tracer to the site of interest . A MI target used in molecular imaging is a molecule or structure in the body to which binds a probe delivered to a specific organ or tissue. The target may be a peptide, or a glucide, or a lipid; in many cases, the target is a protein [10, 11]. Molecular imaging may be a single disease/gene or a general disease/biologic function control point for targeting .
Molecular imaging with transbilayer phospholipid targets may be performed with radiolabelled probes such as radiolabelled annexin V or C2A synaptotagmin domain I or beta 2 glycoprotein I, radiolabelled duramycin, radiolabelled hypericin, radiolabelled lactadherin, radiolabelled choline or fluorocholine, radiolabelled diacylglycerols, radiolabelled sphyngomyelin for visualization, characterization and measurement of key biological functions (i.e. apoptosis, necrosis, thrombosis, vasculature endothelium, choline metabolism, myocardial and neuronal phosphoinositide turnover) or for assessing specific diseases (i.e. cancers, immune diseases, inflammatory diseases, infectious diseases, cardiac diseases and neurological diseases).
The membrane bilayer is composed of 40% lipids and glycolipids, and 60% integral proteins and glycoproteins . The lipids in the membrane bilayer are composed of phospholipids (75% to 88%), glycosphyngolipids (2% to 5%) and cholesterol (10% to 20%) . The phospholipids include phosphatidylcholine (45% to 55%), phosphatidylethanolamine (15% to 25%), phosphatidylinositol (10% to 15%), phosphatidylserine (2% to 10%), phosphatidic acid (1% to 2%), sphyngomyelin (5% to 10%) and cardiolipin (2% to 5%). Liposomes are artificial lipid vesicles encapsulating drugs (e.g. chemotherapy drugs, antibiotics, fungicides), enzymes, biological material (e.g. antigens, antibodies) and tracers (e.g. radiolabelled products, contrast agents) . Liposomes are nanoparticles with a diameter < 100 nm characterised by the composition of lipids, the number of membrane bilayers, and the surface charges . The material encapsulated is either dissolved in an aqueous phase or in a lipid phase. Radioactive phospholipid liposomes have been designed for molecular imaging .
Phospholipids are composed of a phosphatidyl tail including a free fatty acid, glycerol and phosphate . In the phospholipid polar head, choline, serine, ethanolamine and inositol bind to the phosphatidyl non-polar tail. Sphingomyelin is the only one cell membrane phospholipid not derived from a glycerol but from an aminoalcohol sphingosine; SM is composed of a core ceramide (i.e. sphingosine and free fatty acid tail) and contains a polar head group composed of phosphocholine or phosphoethanolamine .
PS is an aminophospholipid located in the inner leaflet of the cell membrane. In pathophysiological conditions including apoptosis, thrombosis and tumour vasculature, PS is externalised from the inner leaflet to the outer leaflet of the cell membrane . In necrosis, PS is exposed in the inner leaflet of damaged cells. For SPECT-CT and PET-CT imaging, radiolabelled probes have been designed to target exposed PS with or without the breakdown of cell membrane asymmetry.
C2A domain of synaptotagmin I(C2A) is a 12-kDa protein predominantly located within the synaptic vesicles binding to PS. It has been fused with glutathione-s-transferase (GST) and radiolabelled with 99mTc for imaging of apoptosis or necrosis . In a rat and pig model of acute myocardial infarction, increased 99mTc-C2A-GST uptake was seen in the myocardial infarct area at risk, and was associated with wall dysfunction [34–36]. In a mouse model of NSCLC, increased 99mTc-C2A-GST tumour uptake was noted after paclitaxel chemotherapy-induced apoptosis . Also, C2A-GST has been easily labelled with 18F for early imaging of apoptosis after chemotherapy . In a rabbit model of lung cancer, increased 18F-C2A-GST tumour uptake was detected 72 h after paclitaxel chemotherapy with increased apoptotic index and caspase-3 activity. Recently, the C2A domain of synaptotagmin I has been labelled with a [99mTc(CO)3 +] core by using an efficient C-terminal site-specific radiolabelling method for the imaging of cell death .
PS is not exposed in normal endothelium, but increased exposure of PS is seen on the tumour endothelium vasculature [40, 41]. Bavituximab, a chimeric monoclonal antibody (MW = 145.3 kDa) binding to the beta-2 glycoprotein I domain of PS, has been radiolabelled with the β + emitter arsenicum-74 (74As, T 1/2 = 17.8 days) for tumour vasculature PET imaging, and with the β-,γ emitter 77As (T 1/2 = 38.8 h) for SPECT imaging and potential tumour vasculature endothelium therapy [42–44]. Increased 74As-bavituximab uptake was seen in a rat model of prostate cancer with the highest tumour-to-background activity ratio at 72 h post-i.v injection (at 72 h p.i., tumour-to-liver ratio = 22, and tumour-to-muscle ratio = 470). Using autoradiography and immunohistochemical studies, 74As-bavituximab was found to specifically bind to the tumour endothelium vasculature. Bavituximab radiolabelled with 77As or 76As (β-, T 1/2 = 26.3 h) may be used for dosimetry and immunotherapy.
Hypericin, a non-porphyrin necrosis agent (MW = 504 Da) extracted from St John's wort, has been labelled with 64Cu (β+, T 1/2 = 12.7 h) for PET imaging of necrosis. In a female mouse model of BT474 breast xenograft tumour, 64Cu-bis-DOTA-hypericin demonstrated increased uptake at 24 h post-i.v. injection in necrotic injured tissues treated with near infrared photothermal ablation therapy. PET distribution also showed higher uptake in the liver and the kidneys. Bis-DOTA-hypericin had a selective binding affinity for PS and PE phospholipids . In necrosis, PS and PE are exposed to 64Cu-labelled hypericin probe in the inner leaflet of damaged cell membrane. Hypericin derivatives are efficient and yield reproducible results when radiolabelled with 123I (i.e. mono-123I-iodohypericin and mono-123I-iodohypericin monocarboxylic acid). They have been also used in preclinical models of liver necrosis and myocardial infarction as well as in clinical correlates of these pathophysiologic states [46, 47]. In a preclinical rat model of liver rhabdomyosarcoma, 131I-labelled hypericin was successfully used in theragnostics with a vascular disrupting agent (i.e. combretastatin A4 phosphate or CA4P); high radiolabelling efficiency was noted with minimum deiodination. 131I-hypericin uptake colocalised tumour necrosis within 24 h post-i.v. injection on co-registered planar γ scintigraphy with CT, MRI, histology and autoradiography . Hypericin has also been labelled with 99mTc (i.e. 99mTc-hypericin or 99mTc-mercaptoacetyldiglycyl-1,5-diaminopentylene hypericin-carboxamide) for visualisation of necrotic tissues in rats with reperfused liver infarct . 99mTc-hypericin, however, was found to be not suitable for imaging of necrosis compared to 123I-hypericin derivatives . Although the mechanism of target uptake is unknown, it may be hypothesised that the PS and PE phospholipid targets are involved for 123I-, 131I- and 99mTc-labelled hypericin derivatives, but this is still to be definitely proven.
Lactadherin, a glycoprotein secreted by mammary epithelium, epididymal epithelium, vascular cells and activated macrophages, has been shown to bind in a Ca2+-independent manner and specifically to the C2 domain of PS [51–53]. In vitro, FITC-labelled bovine lactadherin has been used for early detection of apoptosis in leukaemia cell lines treated by etoposide, and also in HeLa cervical cancer lines treated by staurosporine [54, 55]. HYNIC-lactadherin has also been successfully labelled with 99mTc (i.e. 99mTc-HYNIC-lactadherin). In vivo, in a mouse model, 99mTc-HYNIC-lactadherin had a lower uptake in the kidneys compared to 99mTc-HYNIC annexin V. However, this new PS-targeting probe had a higher uptake in the liver, which is a disadvantage for imaging of liver and myocardial apoptosis .
Phosphatidylserine-based radiolabelled molecular imaging probes
apoptosis, necrosis, thrombosis
99mTc, 123I, 111In, 67Ga, 18F, 68Ga, 124I, 64Cu, 94mTc
C2A domain of synaptotagmin I
bavituximab chimeric antibody
tumour endothelium vasculature imaging
tumour endothelium vasculature therapy
99mTc, 123I, 131I
47 - 50
Choline is a main component of biomembranes targeted by the choline kinase enzyme, and is phosphorylated to intracellular phosphocholine and extracellular phosphatidylcholine . Choline has been labelled with 11C (i.e. 11C-choline) and more recently with 18F (i.e. 18F-fluorocholine) for PET-CT imaging [59, 60]. With a longer physical half-life, 18F-fluorocholine (18F-FCH; 18F, T 1/2 = 109 min) is more suitable than 11C-choline (11C, T 1/2 = 20 min) for PET-CT imaging. In human subjects, 18F-FCH showed a fast blood pool clearance with a peak ≤ 5 min post-i.v. injection, a fast tissue uptake and a predominantly renal excretion. Additionally, 18F-FCH biodistribution changes very slowly later than 10 min after i.v. injection .
18 F-fluorocholine (18F-FCH) and 11 C-choline are incorporated into the membrane phospholipids, and are predominantly used for prostate cancer imaging and brain tumour imaging [62, 63]. In prostate cancer patients, 18F-FCH is a promising tracer for detection of primary prostate cancer, staging of lymph node and bone metastases, and detection of recurrence after definitive therapy [62–64]. In brain tumours, this agent may be useful to detect glioblastoma multiforme, to distinguish high-grade gliomas with a characteristic peri-tumoural uptake from metastases and benign lesions, to guide a stereotactic biopsy, and also to differentiate post-radiation necrosis from recurrence [65–68]. Also, 11C-choline and 18F-FCH have been used for hepatocellular carcinoma (HCC) imaging [69–71]. In a woodchuck model, 11C-choline sensitivity for detection of well-differentiated HCCs was higher than that of 18F-FDG, and in 12 patients with moderately differentiated HCCs, the 11C-choline detection rate was better than that of 18F-FDG. 18F-FCH imaging has also successfully been performed for detection of well-differentiated HCC in patients with liver nodules or cirrhosis or chronic liver disease, and for detection of recurrences from HCC [72, 73].
Phosphatidylcholine-based radiolabelled molecular imaging probes
PE is primarily located in the inner leaflet of the membrane bilayer . Like PS, this major aminophospholipid is externalised from the inner leaflet to the outer leaflet of the cell membrane during apoptosis and tumour vascular endothelium [89, 90]. In necrosis, PE is exposed in the inner leaflet of disintegrated cell membrane.
In addition to this, radiolabelled ethanolamine (i.e. ethanolamine labelled with 11C or 18F) is a potential new probe in oncology PET-CT imaging for assessment of tumour proliferation . 14 C-ethanolamine has been used in a variety of tumour cell types (i.e. melanoma, prostate cancer, glioblastoma multiforme, diffuse large B-cell lymphoma, colorectal adenocarcinoma). 14C-ethanolamine is incorporated into PE and has a two- to sevenfold significantly better uptake into tumour cell types than 14C-choline. In an in vitro model of cultured prostate cancer cells, 14C-ethanolamine and 14 C-N, N'-dimethyl-ethanolamine uptake was two- to fourfold better in androgen-dependent and proliferating PC3 cells compared to androgen-independent and growth-arrested LnCap cells.
Phosphatidylethanolamine-based radiolabelled molecular imaging probes
ethanolamine metabolism (tumour proliferation)
123I, 131I 99mTc
PI phospholipid is located in the inner leaflet of the membrane bilayer . 1,2 Diacylglycerol (DAG) is metabolised to intermediate phosphoinositide metabolites (i.e. PA, PIP, PIP2, PIP3) including phosphatidylinositol (PI) . DAG activates the intracellular protein kinase C (PKC) transduction signalling pathway, which is involved in higher cortical functions (e.g. memory, learning) and cardiac functions (e.g. hypertrophic growth, ventricular remodelling).
Intact 11 C-inositol (i.e. non-acetylated inositol) has been suggested as a diagnostic agent in PET imaging for evaluation of PI brain metabolism and its role as second messenger . In a rat and monkey model, 1-[1-11C]-butyryl-2-palmitoyl-rac-glycerol or 11 C-DAG has been designed as a PI-targeting probe in PET brain imaging to visualise neuronal PI turnover [97, 98]. 11C-DAG levels are low in the brain, and thus it may be appropriately used to visualise PI metabolism in the central nervous system. Dynamic PET imaging showed increased 11C-DAG uptake in the first 15 min with an equilibrium at 16 min in pre-stimulation and post-stimulation conditions, which is suggestive of a membrane trapping mechanism. 11C-DAG uptake increased 20% to 30% after arecoline stimulation (i.e. acetylcholine muscarinic receptor stimulation), which suggests that 11C-DAG is a tracer of the transduction signalling PI-mediated pathway. In resting conditions, 11C-DAG uptake was observed in the visual association area, and increased in the whole brain and the occipital areas after arecoline stimulation. In C6 glioma cells implanted in the rat brain, 11C-DAG was rapidly incorporated in the PI turnover within 5 min post-i.v injection; in a patient with astrocytoma grade III, 11C-DAG was gradually incorporated in the leading PI turnover and the PE-PC secondary pool with an equilibrium period at 32-40 min post-iv. injection . In patients with Alzheimer's disease and ischemic stroke, 11C-DAG evaluated the PI cortical function and neural viability, respectively. In eight patients with Alzheimer's disease, 18F-FDG PET imaging showed bilateral hypometabolism in the parieto-temporal association areas, while 11C-DAG imaging showed spotty uptake in the frontal lobes of the brain suggestive of compensatory plastic process in non-damaged neural circuits to degenerative cognitive impairment . In five patients with cerebral infarction, dynamic PET brain imaging showed decreased 11C-DAG uptake in comparison to normal cortex . 11C-DAG pharmacokinetics demonstrated rapid decrease in the plasma with a peak at 40 s post-i.v. injection, and gradual increase in the brain to reach a plateau at 15 to 20 min post-i.v. injection. Reflecting neural signal transduction activity, the incorporation constant of 11C-DAG (k*DAG) was best correlated with the cerebral metabolic rate of O2 (CMRO2). Maintained PI metabolism suggested preservation of neural viability in the peri-infarct area of the ischemic stroke. Patients with subacute local brain injury, either ischemic stroke or brain tumour, also exhibited 11C-DAG spots located in the associative areas distant from the lesion between 2 weeks and 1 month after injury; one of the possible features of neural recovery in the intact brain related to PI metabolism in PET imaging .
Phosphatidylinositol-based radiolabelled molecular imaging probes
PI brain metabolism
PI myocardial turnover
PI neuronal turnover
SM is a cholinophospholipid located in the outer leaflet of the membrane bilayer . Liposomes composed of SM have been experimentally used for tumour imaging. In a mouse tumour model, serum stable SM liposomes- encapsulating 67Ga prepared in a lipid phase with cholesterol (SM/cholesterol molar ratio, 2:1) enhanced blood circulation and increased 67Ga delivery to the tumour . Tumour-to-blood activity ratio (T/B) and tumour index (TI = T/B × percentage dose per gram) were higher at 24, 48 and 72 h post-injection.
Sphyngomyelin-based radiolabelled molecular imaging probes
the PS target allows the visualisation, characterisation, and measurement of apoptosis or necrosis, and thrombosis with radiolabelled annexin V and the 99mTc or 18F-labelled C2A domain of synaptotagmin I and the 99mTc-labelled HYNIC-lactadherin; 99mTc-labelled synthetic PSBP-6-SAAC probe has been designed for molecular imaging of cell death. PS targeting probes may allow imaging of tumour endothelium vasculature with 74As-bavituximab. 77/76As-bavituximab may also serve for β- radioimmunotherapy of tumours with PS exposed endothelium tumour vasculature.
the PE target allows imaging of apoptosis or necrosis with 99mTc-HYNIC-duramycin. It may also allow tumour imaging with radiolabelled ethanolamine and N,N' dimethylethanolamine.
the PS and PE targets allow imaging of necrosis with the radiolabelled 64Cu-bis-DOTA hypericin.
the PC target allows assessment of choline metabolism with 11C-choline or 18F-fluorocholine, and also the evaluation of the acetate and acetoacetate metabolism with 11C-acetate or 18F-fluoroacetate and 11C-acetoacetate.
the PI target allows evaluation of the neuronal and myocardial PI turnover with 11C or 18F-labelled DAG, and also with 11C-inositol.
the SM target may be used with liposomes encapsulating 67Ga for imaging purposes.
Translation of preclinical research to clinical research will be necessary to optimally assess the pharmacokinetics of radiolabelled probes for molecular imaging of transbilayer phospholipids.
TB is nuclear medicine physician (MD, PhD) and Adjunct Professor at The University of Western Ontario in the department of Medical Imaging (London, ON, Canada).
FP is imaging program leader (PhD), Assistant Scientific Director at The Lawson Health Research Institute (LHRI), Professor at The University of Western Ontario in the departments of Medical Imaging, Medical BioPhysics and Physics, and Chief Medical Physicist at St. Joseph's Health Care and London Health Sciences Centre (London, ON, Canada).
C2A Synaptotagmin domain I glutathione-S-transferase
combretastatin A4 phosphate
1,4,7,10-tetraazacyclododecane-N, N', N″, N″'-tetraacetic acid
external leaflet of the cell membrane
id est (in example with complete enumeration)
exampli gratia (for example with incomplete enumeration)
internal leaflet of the cell membrane
- 10-9 M:
magnetic resonance imaging
non-small cell lung cancer
positron emission tomography-computed tomography
- PIP 2:
- PIP 3:
single amino acid chelator
single-photon emission computed tomography-computed tomography
tumour necrosis factor-related apoptosis-inducing ligand
terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling.
The authors would like to acknowledge the contribution of Dr. Kimberley J. Blackwood (PhD), post-doctoral associate at The University of Western Ontario and The Lawson Health Research Institute, for her valuable assistance in the manuscript editing.
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