Biologically important processes in normal brain function and brain disease involve the action of various protein-based receptors, ion channels, transporters and enzymes. The ability to interrogate the location, abundance and activity of these entities in vivo using non-invasive molecular imaging can provide unprecedented information about the spatio-temporal dynamics of brain function. Indeed, positron emission tomography (PET) imaging is transforming our understanding of the central nervous system and brain disease. Great emphasis has historically been placed on developing radioligands for the non-invasive detection of neuroreceptors. In contrast, relatively few enzymes have been amenable to examination by PET imaging procedures based upon trapping or accumulation of enzymatic products, because only a subset of enzymes have sufficient catalytic rate to produce measureable accumulation within the practical time-limit of PET recordings. However, high affinity inhibitors are now serving as tracers for enzymes, particularly for measuring the abundance of enzymes mediating intracellular signal transduction in the brain, which offer a rich diversity of potential targets for drug discovery. The purpose of this review is to summarize well-known radiotracers for brain enzymes, and draw attention to recent developments in PET radiotracers for imaging signal transduction pathways in the brain. The review is organized by target class and focuses on structural chemistry of the best-established radiotracers identified in each class.
Positron emission tomography; monoamines; second messengers; kinase inhibitors; esterases
Novel imaging modalities are required to better identify vulnerable atherosclerotic plaques before their dire consequences of myocardial infarction, sudden death, and stroke. Moving beyond traditional diagnostic methods, the field of molecular imaging offers an innovative approach to report upon critical in vivo biological features of high-risk plaques. Molecular imaging employs engineered, targeted imaging agents in conjunction with sophisticated, high-resolution detection systems. While various modalities have been investigated for this purpose, intravascular near infrared fluorescence imaging (NIRF) strategies are uniquely poised to provide high-resolution readouts of human coronary artery plaques. To date, preclinical animal studies have demonstrated feasibility of both standalone NIRF intravascular imaging as well as dual-modality approaches detecting inflammation and fibrin deposition in coronary-sized arteries. This translatable catheter-based approach is positioned to advance the identification of biologically vulnerable coronary plaques and coronary stents at risk of thrombosis.
Near-infrared intravascular imaging; atherosclerosis; coronary; vulnerable plaque; inflammation; coronary stenting
Stem-cell-based therapies hold promise and potential to address many unmet clinical needs. Cell tracking with modern imaging modalities offers insight into the underlying biological process of the stem-cell-based therapies, with the goal to reveal cell survival, migration, homing, engraftment, differentiation, and functions. Adaptability, sensitivity, resolution, and non-invasiveness have contributed to the longstanding use of optical imaging for stem cell tracking and analysis. To identify transplanted stem cells from the host tissue, optically active probes are usually used to label stem cells before the administration. In comparison to the traditional fluorescent probes like fluorescent proteins and dyes, nanoparticle-based probes are advantageous in terms of the photo-stabilities and minimal changes to the cell phenotype. The main focus here is to overview the recent development of optically active nanoparticles for stem cells tracking. The related optical imaging modalities include fluorescence imaging, photoacoustic imaging, Raman and surface enhanced Raman spectroscopy imaging.
Stem cell therapy; optical imaging; nanoparticles; fluorescence imaging; photoacoustic imaging; Raman and surface enhanced Raman spectroscopy imaging
Recent advances in molecular and cellular biology have facilitated the discovery of the key molecular drivers of major diseases. This knowledge raised some optimism in the beginning of this century, yet its impact on disease prevention, diagnosis and targeted intervention remains low. At the same time the pharmaceutical industry is facing the dual challenges of a dwindling drug pipeline and ever increasing cost of drug development. It is against this background that a number of European countries decided to establish EATRIS, the European Advanced Translational Research InfraStructure in Medicine. EATRIS aims for faster and more efficient translation of basic research into innovative products, by providing academia and industry access to the state-of-the-art expertise and highly capital-intensive facilities residing in Europe’s top translational research centers and hospitals. To this end, EATRIS formed product groups that provide translational services in the fields of development and supply of (1) molecular imaging and tracing, (2) vaccines, (3) biomarkers, (4) small molecules and (5) advanced therapeutic medicinal products. Herein we describe the background, goals, functions and structure of EATRIS. As an example, it will be described how EATRIS centers involved in imaging and tracing might contribute to more efficient drug development and personalized medicine.
Drug development; european advanced translational research infrastructure (EATRIS); immuno-positron emission tomography; molecular imaging; personalized medicine; tyrosine kinase inhibitor-positron emission tomography; translational research
Tumor microenvironment plays important roles in tumor development and metastasis. Features of the tumor microenvironment that are significantly different from normal tissues include acidity, hypoxia, overexpressed proteases and so on. Therefore, these features can serve as not only biomarkers for tumor diagnosis but also theraputic targets for tumor treatment. Imaging modalities such as optical, positron emission tomography (PET) and magnetic resonance imaging (MRI) have been intensively applied to investigate tumor microenvironment. Various imaging probes targeting pH, hypoxia and proteases in tumor microenvironment were thus well developed. In this review, we will focus on recent examples on fluorescent probes for optical imaging of tumor microenvironment. Construction of these fluorescent probes were based on characteristic feature of pH, hypoxia and proteases in tumor microenvironment. Strategies for development of these fluorescent probes and applications of these probes in optical imaging of tumor cells or tissues will be discussed in this review paper.
Optical imaging; tumor microenvironment; pH; hypoxia; protease
Cardiovascular disease is the leading cause of death worldwide. Unstable atherosclerotic plaques are prone to rupture followed by thrombus formation, vessel stenosis, and occlusion and frequently lead to acute myocardial infarction and brain infarction. As such, unstable plaques represent an important diagnostic target in clinical settings and the specific diagnosis of unstable plaques would enable preventive treatments for cardiovascular disease. To date, various imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and intravascular ultrasound (IVUS) have been widely used clinically. Although these methods have advantages in terms of spatial resolution and the ability to make detailed identification of morphological alterations such as calcifications and vessel stenosis, these techniques require skill or expertise to discriminate plaque instability, which is essential for early diagnosis and treatment and can present difficulties for quantitative estimation. On the other hand, nuclear imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) can noninvasively collect quantitative information on the expression levels of functional molecules and metabolic activities in vivo and thus provide functional diagnoses of unstable plaques with high sensitivity. Specifically, unstable plaques are characterized by an abundance of invasive inflammatory cells (macrophages), increased oxidative stress that increases oxidized LDL and its receptor expressed on cells in the lesions, increased occurrence of apoptosis of macrophages and other cells involved in disease progression, increased protease expression and activity, and finally thrombus formation triggered by plaque rupture, which is the most important mechanism leading to the onset of infarctions and ischemic sudden death. Therefore, these characteristics can all be targets for molecular imaging by PET and SPECT. In this paper, we review the present state and future of radiolabelled probes that have been developed for detecting atherosclerotic unstable plaques with nuclear imaging techniques.
Molecular imaging; atherosclerosis; plaque; positron emission tomography; single photon emission computed tomography; 2-[18F]Fluoro-2-deoxy-D-glucose; lectin-like oxidized low density lipoprotein receptor-1; apoptosis; matrix metalloproteinase; thrombus
Platinum based drugs are widely used to treat various types of cancers by inducing DNA damage mediated cytotoxicity. However, acquirement of chemoresistance towards platinum based drugs is a common phenomenon and a major hurdle in combating the relapse of the disease. Oncogenesis and chemoresistance are multifactorial maladies which often involve deregulation of one of the prime cell survival pathways, the PI3K/Akt/mTOR signalling cascade. The genetic alterations related to this pathway are often responsible for initiation and/or maintenance of carcinogenesis. Molecular components of this pathway are long being recognized as major targets for therapeutic intervention and are now also have emerged as potential tools for diagnosis of cancer. To develop novel therapeutics against the key molecules of PI3K pathway, stringent validation is required using both in-vitro and in-vivo models. Repetitive and non-invasive molecular imaging techniques, a relatively recent field in biomedical imaging hold great promises for monitoring such diagnosis and therapy. In this review, we first introduced the PI3K/Akt/mTOR pathway and its role in acquirement of chemoresistance in various cancers. Further we described how non-invasive molecular imaging approaches are sought to use this PI3K signalling axis for the therapeutics and diagnosis. A theranostic approach using various imaging modalities should be the future of PI3K signalling based drug development venture.
PI3K signalling; platinum based chemoresistance; repetitive and non-invasive molecular imaging techniques; PET imaging; bioluminescence imaging; Akt sensor; fluorescence imaging
After more than 20 years of research, a fully integrated PET/MR scanner was launched in 2010 enabling simultaneous acquisition of PET and MR imaging. Currently, no clinical indication for combined PET/MR has been established, however the expectations are high. In this paper we will discuss some of the challenges inherent in this new technology, but focus on potential applications for simultaneous PET/MR in the field of oncology. Methods and tracers for use with the PET technology will be familiar to most readers of this journal; thus this paper aims to provide a short and basic introduction to a number of different MRI techniques, such as DWI-MR (diffusion weighted imaging MR), DCE-MR (dynamic contrast enhanced MR), MRS (MR spectroscopy) and MR for attenuation correction of PET. All MR techniques presented in this paper have shown promising results in the treatment of patients with solid tumors and could be applied together with PET increasing the amount of information about the tissues of interest. The potential clinical benefit of applying PET/MR in staging, radiotherapy planning and treatment evaluation in oncology, as well as the research perspectives for the use of PET/MR in the development of new tracers and drugs will be discussed.
PET/MR; oncology; diagnosis; staging; therapy evaluation; radiotherapy planning; molecular imaging
Diabetes is commonly associated with increased risk of cardiovascular morbidity and mortality. Perturbations in sympathetic nervous system (SNS) signaling have been linked to the progression of diabetic heart disease. Glucose, insulin, and free fatty acids contribute to elevated sympathetic nervous activity and norepinephrine release. Reduced left ventricular compliance and impaired cardiac function lead to further SNS activation. Chronic elevation of cardiac norepinephrine culminates in altered expression of pre- and post-synaptic sympathetic signaling elements, changes in calcium regulatory proteins, and abnormal contraction-excitation coupling. Clinically, these factors manifest as altered resting heart rate, depressed heart rate variability, and impaired cardiac autonomic reflex, which may contribute to elevated cardiovascular risk. Development of molecular imaging probes enable a comprehensive evaluation of cardiac SNS signaling at the neuron, postsynaptic receptor, and intracellular second messenger sites of signal transduction, providing mechanistic insights into cardiac pathology. This review will examine the evidence for abnormal SNS signaling in the diabetic heart and establish the physiological consequences of these changes, drawing from basic biological research in isolated heart and rodent models of diabetes, as well as from clinical reports. Particular attention will be paid to the use of molecular imaging approaches to non-invasively characterize and evaluate sympathetic signal transduction in diabetes, including pre-synaptic norepinephrine reuptake assessment using 11C-meta-hydroxyephedrine (11C-HED) with PET or 123I-metaiodobenzylguanidine (123I-MIBG) with SPECT, and postsynaptic β-adrenoceptor density measurements using CGP12177 derivatives. Finally, the review will attempt to define the future role of these non-invasive nuclear imaging techniques in diabetes research and clinical care.
Sympathetic neuronal imaging; SNS signaling; norepinephrine; β-adrenoceptor; norepinephrine reuptake transporter
Radioiodine whole-body scintigraphy (WBS), which takes advantage of the high avidity of radioiodine in the functioning thyroid tissues, has been used for detection of differentiated thyroid cancer. Radioiodine is a sensitive marker for detection of thyroid cancer; however, radioiodine uptake is not specific for thyroid tissue. It can also be seen in healthy tissue, including thymus, breast, liver, and gastrointestinal tract, or in benign diseases, such as cysts and inflammation, or in a variety of benign and malignant non-thyroidal tumors, which could be mistaken for thyroid cancer. In order to accurately interpret radioiodine scintigraphy results, one must be familiar with the normal physiologic distribution of the tracer and frequently encountered physiologic and pathologic variants of radioiodine uptake. This article will provide a systematic overview of potential false-positive uptake of radioiodine in the whole body and illustrate how such unexpected findings can be appropriately evaluated.
Differentiated thyroid cancer; radioiodine; I-131; I-123; whole-body scintigraphy; false-positive; physiologic uptake; pathologic uptake
With Alzheimer’s disease (AD) quickly becoming the most costly disease to society, and with no disease-modifying treatment currently, prevention and early detection have become key points in AD research. Important features within this research focus on understanding disease pathology, as well as finding biomarkers that can act as early indicators and trackers of disease progression or potential treatment. With the advances in neuroimaging technology and the development of new imaging techniques, the search for cheap, noninvasive, sensitive biomarkers becomes more accessible. Modern neuroimaging techniques are able to cover most aspects of disease pathology, including visualization of senile plaques and neurofibrillary tangles, cortical atrophy, neuronal loss, vascular damage, and changes in brain biochemistry. These methods can provide complementary information, resulting in an overall picture of AD. Additionally, applying neuroimaging to animal models of AD could bring about greater understanding in disease etiology and experimental treatments whilst remaining in vivo. In this review, we present the current neuroimaging techniques used in AD research in both their human and animal applications, and discuss how this fits in to the overall goal of understanding AD.
Alzheimer’s disease; animal models; ASL; biomarkers; MRI; MRS; neuroimaging; PET
Cerenkov luminescence imaging (CLI) is an emerging hybrid modality that utilizes the light emission from many commonly used medical isotopes. Cerenkov radiation (CR) is produced when charged particles travel through a dielectric medium faster than the speed of light in that medium. First described in detail nearly 100 years ago, CR has only recently applied for biomedical imaging purposes. The modality is of considerable interest as it enables the use of widespread luminescence imaging equipment to visualize clinical diagnostic (all PET radioisotopes) and many therapeutic radionuclides. The amount of light detected in CLI applications is significantly lower than other that in other optical imaging techniques such as bioluminescence and fluorescence. However, significant advantages include the use of approved radiotracers and lack of an incident light source, resulting in high signal to background ratios. As well, multiple subjects may be imaged concurrently (up to 5 in common bioluminescent equipment), conferring both cost and time benefits. This review summarizes the field of Cerenkov luminescence imaging to date. Applications of CLI discussed include intraoperative radionuclide-guided surgery, monitoring of therapeutic efficacy, tomographic optical imaging capabilities, and the ability to perform multiplexed imaging using fluorophores excited by the Cerenkov radiation. While technical challenges still exist, Cerenkov imaging has materialized as an important molecular imaging modality.
Cerenkov radiation; PET; optical imaging; fluorescence
As remission has now become a realistic therapeutic goal in the clinical management of RA due to the introduction and widespread adoption of biologic agents, there is a greater need for earlier diagnoses and objective methods for evaluating disease activity and response to treatment. In this capacity, advanced imaging strategies are assuming an expansive clinical role, particularly as they take advantage of newer imaging technologies and the shift toward imaging at the molecular level. Molecular imaging utilizes target-specific probes to non-invasively visualize molecular, cellular, and physiological perturbations in response to the underlying pathology. Probes for nuclear and MR imaging have been and are being developed that react with discrete aspects of inflammatory and destructive pathways specific to RA. These probes in addition to new MR sequences and contrast agents have the potential to provide an earlier and more reliable assessment of clinical outcome, disease activity, severity, and location, and therapeutic response. Furthermore, these imaging strategies may enable a more fundamental understanding of critical pathophysiological processes and the advent of new molecular therapies. This review will discuss these advances in both nuclear medicine and MRI strategies for imaging RA with a particular emphasis on molecular imaging.
Molecular imaging; magnetic resonance imaging; nuclear imaging; rheumatoid arthritis
Insulin-like growth factor 1 receptor (IGF1R) plays an important role in proliferation, apoptosis, angiogenesis, and tumor invasion. Histology and in situ hybridization studies have revealed that IGF1R was significantly up-regulated at the protein and mRNA level in many types of cancer. Since measuring IGF1R expression with immunohistochemistry has many limitations, non-invasive imaging of IGF1R can allow for more accurate patient stratification (e.g. selecting the right patient population for IGF1R-targeted therapy) and more effective monitoring of the therapeutic responses in cancer patients. In this review, we will summarize the current status of imaging IGF1R expression in cancer, which includes single-photon emission computed tomography, positron emission tomography, fluorescence, and γ-camera imaging. The four major classes of ligands that have been developed for non-invasive visualization of IGF1R will be discussed: proteins, antibodies, peptides, and affibodies. To date, molecular imaging of IGF1R expression is understudied and more research effort is needed in the future.
Insulin-like growth factor 1 receptor (IGF1R); molecular imaging; peptide nucleic acid (PNA); positron emission tomography (PET); single-photon emission computed tomography (SPECT); cancer
Surface enhanced Raman scattering (SERS) is a signal-increasing phenomenon that occurs whenever Raman scattering on a metal surface is enhanced many orders of magnitude. Recently SERS has received considerable attention due to its ultrasensitive multiplex imaging capability with strong photostability. It provides rich molecular information on any Raman molecule adsorbed to rough metal surfaces. The signal enhancement is so remarkable that identification of a single molecule is possible. SERS has become a genuine molecular imaging technique. Gold nanoparticles, encoded with Raman reporters, provide a SERS signal and have been used as imaging probes, often referred to as SERS nanoparticles. They have been used for molecular imaging in vivo, ex vivo and in vitro. Detection of picomolar concentrations of target molecules has been achieved by functionalizing the nanoparticles with target recognition ligands. This review focuses on recent achievements in utilizing SERS nanoparticles for in vivo molecular imaging. In the near future, SERS technology may allow detection of disease markers at the single cell level.
SERS; gold nanoparticle; Raman; molecular imaging; cancer; SERS nanoparticle
Positron Emission Tomography (PET) is a nuclear medicine imaging technique that is widely used in early detection and treatment follow up of many diseases, including cancer. This modality requires positron-emitting isotope labeled biomolecules, which are synthesized prior to perform imaging studies. Fluorine-18 is one of the several isotopes of fluorine that is routinely used in radiolabeling of biomolecules for PET; because of its positron emitting property and favorable half-life of 109.8 min. The biologically active molecule most commonly used for PET is 2-deoxy-2-18F-fluoro-β-D-glucose (18F-FDG), an analogue of glucose, for early detection of tumors. The concentrations of tracer accumulation (PET image) demonstrate the metabolic activity of tissues in terms of regional glucose metabolism and accumulation. Other tracers are also used in PET to image the tissue concentration. In this review, information on fluorination and radiofluorination reactions, radiofluorinating agents, and radiolabeling of various compounds and their application in PET imaging is presented.
Fluorine-18; positron emission tomography (PET); PET radiopharmaceuticals
The aim of this review is to evaluate clinical applications of 11C-acetate positron emission tomography (PET). Acetate is quickly metabolized into acetyl-CoA in human cells. In this form it can either enter into the tricarboxylic acid cycle, thus producing energy, as happens in the myocardium, or participate in cell membrane lipid synthesis, as happens in tumor cells. 11C-acetate PET was originally employed in cardiology, to study myocardial oxygen metabolism. More recently it has also been used to evaluate myocardial perfusion, as well as in oncology. The first studies of 11C-acetate focused on its use in prostate cancer. Subsequently, 11C-acetate was studied in other urological malignancies, as well as renal cell carcinoma and bladder cancer. Well differentiated hepatocellular carcinoma represents an 18F-fluoro-deoxyglucose (18F-FDG) PET pitfall, so many authors have proposed to use 11C-acetate in addition to 18F-FDG in studying this tumor. 11C-acetate PET has also been used in other malignancies, such as brain tumors and lung carcinoma. Some authors reported a few cases in which 11C-acetate PET incidentally found multiple myeloma or rare tumors, such as thymoma, multicentric angiomyolipoma of the kidney and cerebellopontine angle schwannoma. Lastly, 11C-acetate PET was also employed in a differential diagnosis case between glioma and encephalitis. The numerous studies on 11C-acetate have demonstrated that it can be used in cardiology and oncology with no contraindications apart from pregnancy and the necessity of a rapid scan. Despite its limited availability, this tracer can surely be considered to be a promising one, because of its versatility and capacity to even detect non 18F-FDG-avid neoplasm, such as differentiated lung cancer or hepatocellular carcinoma.
Positron emission tomography (PET); 11C-acetate; cancer; cardiology; prostate cancer; liver cancer; brain tumor
Molecular imaging allows direct visualization of targets and characterization of cellular pathways, as long as a high signal/background ratio can be achieved, which requires a sufficient amount of probes to accumulate in the imaging region. The Asn-Gly-Arg (NGR) tripeptide selected by phage display can specifically target tumor vasculature. Recognizing the aminopeptidase N (APN or CD13) receptor on the membrane of tumor cells, the peptide can be further internalized into cytoplasma by the endosomal pathway. Hence NGR can serve as an ideal candidate for tumor imaging, once it is conjugated with fluorescent or radiolabeled imaging probes. Herein, we highlight some recent developments of NGR peptide based imaging of tumors. Although still in the preliminary stage, some NGR probes have shown potential as promising agents in future clinical applications.
Asparagine-glycine-arginine (NGR); arginine-glycine-aspartic acid (RGD); isoaspartate-glycine-arginine (isoDGR); cancer; imaging; tumor angiogenesis; vasculature; aminopeptidase N (APN/CD13)
Sarcomas are a biologically complex group of diseases that exhibit variable responses to single or combination therapy. 18F-FDG PET imaging contributes to sarcoma treatment response assessment as an objective semiquantitative biomarker of response. In this review, background and experience in 18F-FDG PET as a biomarker that successfully identifies tumor response is assessed.
18F-FDG PET; sarcoma; imaging treatment response