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1.  In vivo molecular imaging of cancer stem cells 
A rare subpopulation of cancer cells known as cancer stem cells (CSCs) have distinct characteristics resembling stem cells, including cell renewal capability, differentiation into multiple lineages, and endless proliferation potential. Cumulating evidence has revealed that CSCs are responsible for tumorigenicity, invasion, metastasis, and therapeutic resistance. Despite continued investigation of CSCs, in vivo behavior of CSCs is not yet fully understood. The in vivo imaging modalities of optical, nuclear, and magnetic resonance are currently being employed to investigate the complexity behind the CSCs behavior. Valuable information that were previously obscured by the limitations of in vitro techniques now are currently being revealed. These studies give us a more comprehensive insight about what happen to CSCs in vivo. This review will briefly discuss the recent findings on CSCs behavior as informed by in vivo imaging studies.
PMCID: PMC4299772  PMID: 25625023
Cancer stem cell; MRI; PET; fluorescence imaging; in vivo imaging; molecular imaging; cell tracking
2.  The sweet spot: FDG and other 2-carbon glucose analogs for multi-modal metabolic imaging of tumor metabolism 
Multi-modal imaging approaches of tumor metabolism that provide improved specificity, physiological relevance and spatial resolution would improve diagnosing of tumors and evaluation of tumor progression. Currently, the molecular probe FDG, glucose fluorinated with 18F at the 2-carbon, is the primary metabolic approach for clinical diagnostics with PET imaging. However, PET lacks the resolution necessary to yield intratumoral distributions of deoxyglucose, on the cellular level. Multi-modal imaging could elucidate this problem, but requires the development of new glucose analogs that are better suited for other imaging modalities. Several such analogs have been created and are reviewed here. Also reviewed are several multi-modal imaging studies that have been performed that attempt to shed light on the cellular distribution of glucose analogs within tumors. Some of these studies are performed in vitro, while others are performed in vivo, in an animal model. The results from these studies introduce a visualization gap between the in vitro and in vivo studies that, if solved, could enable the early detection of tumors, the high resolution monitoring of tumors during treatment, and the greater accuracy in assessment of different imaging agents.
PMCID: PMC4299774  PMID: 25625022
Glucose; glucose uptake; FDG; deoxyglucose; FDG-PET; multi-modal imaging
3.  Kinetic modeling in PET imaging of hypoxia 
Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET contains additional valuable information on the temporal changes in tracer distribution. Kinetic modeling can be used to extract relevant pharmacokinetic parameters of tracer behavior in vivo that reflects relevant physiological processes. In this paper, we review the potential contribution of kinetic analysis for PET imaging of hypoxia.
PMCID: PMC4171837  PMID: 25250200
Cu-ATSM; 18F-FMISO; 18F-FETNIM; 18F-FAZA; oxygenation
4.  Recent advances in diagnosis and treatment of gliomas using chlorotoxin-based bioconjugates 
Malignant gliomas, especially glioblastoma multiforme, are the most widely distributed and deadliest brain tumors because of their resistance to surgical and medical treatment. Research of glioma-specific bioconjugates for diagnosis and therapy developed rapidly during the past several years. Many studies have demonstrated that chlorotoxin (CTX) and Buthus martensii Karsch chlorotoxin (BmK CT) specifically inhibited glioma cells growth and metastasis, and accelerated tumor apoptosis. The bioconjugates of CTX or BmK CT with other molecules have played an increasing role in diagnostic imaging and treatment of gliomas. To date, CTX-based bioconjugates have achieved great success in phase I/II clinical trials about safety profiles. Here, we will provide a review on the important role of ion channels in the underlying mechanisms of gliomas invasive growth and how CTX suppresses gliomas proliferation and migration. We will summarize the recent advances in the applications of CTX bioconjugates for gliomas diagnosis and treatment. In addition, we will review recent studies on BmK CT bioconjugates and compare their efficacies with CTX derivatives. Finally, we will address advantages and challenges in the use of CTX or BmK CT bioconjugates as specific agents for theranostic applications in gliomas.
PMCID: PMC4138135  PMID: 25143859
Chlorotoxin (CTX); Buthus martensii Karsch chlorotoxin (BmK CT); glioma; imaging; therapy
5.  The role of molecular imaging in diagnosis of deep vein thrombosis 
Venous thromboembolism (VTE) mostly presenting as deep venous thrombosis (DVT) and pulmonary embolism (PE) affects up to 600,000 individuals in United States each year. Clinical symptoms of VTE are nonspecific and sometimes misleading. Additionally, side effects of available treatment plans for DVT are significant. Therefore, medical imaging plays a crucial role in proper diagnosis and avoidance from over/under diagnosis, which exposes the patient to risk. In addition to conventional structural imaging modalities, such as ultrasonography and computed tomography, molecular imaging with different tracers have been studied for diagnosis of DVT. In this review we will discuss currently available and newly evolving targets and tracers for detection of DVT using molecular imaging methods.
PMCID: PMC4138136  PMID: 25143860
FDG-PET/CT; venous thromboembolism; deep vein thrombosis; SPECT; molecular imaging
6.  The value of 68Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature 
Neuroendocrine tumors (NETs) are rare group of neoplasms arising from nervous and endocrine systems. Somatostatin analogue imaging is a functional imaging modality of choice for evaluating the NETs. Recent availability of positron emitting radioisotope labeled somatostatin analogues to image neuroendocrine cancers, has raised the interests to use this new imaging modality in management of patients with NETs. 68Ga-DOTATATE PET/CT has demonstrated superiority in lesion detection compared to Octreoscan, MIBG scintigraphy and MRI. In this article, we reviewed the published studies evaluating the role of 68Ga-DOTATATE PET in diagnosis and management of patients with neuroendocrine tumors and comparing it to current FDA approved imaging modalities including Octreoscan, MIBG scintigraphy, 18F FDG PET/CT, CT and MRI.
PMCID: PMC4138137  PMID: 25143861
Gallium 68; neuroendocrine tumors; DOTATATE; positron emission tomography; hybrid imaging
7.  Molecular imaging of integrin αvβ6 expression in living subjects 
Integrins, a family of cell adhesion molecules composed of α and β heterodimeric subunits, are involved in a wide range of cell-extracellular matrix and cell-cell interactions. The study of integrin family members as targets for molecular imaging and therapy has been generally limited with the exception of integrin αvβ3. vβ6, a member of the integrin family, is expressed at low or undetectable levels in normal tissues, but is widely upregulated during many pathological and physiological processes, especially cancer and fibrosis, making it a promising target for molecular imaging. Noninvasive and quantitative imaging of integrin vβ6 expression would be very useful for disease diagnosis, treatment monitoring, and prognosis assessment. Although various molecular probes have been developed for positron emission tomography and single-photon emission computed tomography imaging of integrin vβ6 expression in preclinical animal models, further research efforts are required to optimize integrin vβ6-targeting probes for future potential clinical applications in the fields of oncology and beyond.
PMCID: PMC4074499  PMID: 24982819
Molecular probe; noninvasive imaging; positron emission tomography (PET); single-photon emission computed tomography (SPECT); cancer; fibrosis; wound healing
8.  PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence  
Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resolution, three-dimensional tumor representation, possibility of semiquantification/quantification of the amount of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compounds in the early 1980s, a great number of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls.
PMCID: PMC4074502  PMID: 24982822
Hypoxia; tumor imaging; PET; 18F-FDG; 18F-FMISO; 18F-FAZA; 64Cu-ATSM
9.  Bioorthogonal chemistry: implications for pretargeted nuclear (PET/SPECT) imaging and therapy 
Due to their rapid and highly selective nature, bioorthogonal chemistry reactions are attracting a significant amount of recent interest in the radiopharmaceutical community. Over the last few years, reactions of this type have found tremendous utility in the construction of new radiopharmaceuticals and as a method of bioconjugation. Furthermore, reports are beginning to emerge in which these reactions are also being applied in vivo to facilitate a novel pretargeting strategy for the imaging and therapy of cancer. The successful implementation of such an approach could lead to dramatic improvements in image quality, therapeutic index, and reduced radiation dose to non-target organs and tissues. This review will focus on the potential of various bioorthogonal chemistry reactions to be used successfully in such an approach.
PMCID: PMC3992206  PMID: 24753979
Pretargeting; bioorthogonal chemistry; molecular imaging; PET; SPECT; click chemistry
10.  Modeling and imaging cardiac sympathetic neurodegeneration in Parkinson’s disease 
Parkinson’s disease (PD) is currently recognized as a multisystem disorder affecting several components of the central and peripheral nervous system. This new understanding of PD helps explain the complexity of the patients’ symptoms while challenges researchers to identify new diagnostic and therapeutic strategies. Cardiac neurodegeneration and dysautonomia affect PD patients and are associated with orthostatic hypotension, fatigue, and abnormal control of electrical heart activity. They can seriously impact daily life of PD patients, as these symptoms do not respond to classical anti-parkinsonian medications and can be worsened by them. New diagnostic tools and therapies aiming to prevent cardiac neurodegeneration and dysautonomia are needed. In this manuscript we critically review the relationship between the cardiovascular and nervous system in normal and PD conditions, current animal models of cardiac dysautonomia and the application of molecular imaging methods to visualize cardiac neurodegeneration. Our goal is to highlight current progress in the development of tools to understand cardiac neurodegeneration and dysautonomia and monitor the effects of novel therapies aiming for global neuroprotection.
PMCID: PMC3992208  PMID: 24753981
Positron emission tomography; SPECT; 18F-FDA; 11C-MHED; cardiac dysautonomia; sympathetic nervous system; Parkinson’s disease
11.  Clinical oncologic applications of PET/MRI: a new horizon 
Positron emission tomography/magnetic resonance imaging (PET/MRI) leverages the high soft-tissue contrast and the functional sequences of MR with the molecular information of PET in one single, hybrid imaging technology. This technology, which was recently introduced into the clinical arena in a few medical centers worldwide, provides information about tumor biology and microenvironment. Studies on indirect PET/MRI (use of positron emission tomography/computed tomography (PET/CT) images software fused with MRI images) have already generated interesting preliminary data to pave the ground for potential applications of PET/MRI. These initial data convey that PET/MRI is promising in neuro-oncology and head & neck cancer applications as well as neoplasms in the abdomen and pelvis. The pediatric and young adult oncology population requiring frequent follow-up studies as well as pregnant woman might benefit from PET/MRI due to its lower ionizing radiation dose. The indication and planning of therapeutic interventions and specifically radiation therapy in individual patients could be and to a certain extent are already facilitated by performing PET/MRI. The objective of this article is to discuss potential clinical oncology indications of PET/MRI.
PMCID: PMC3992213  PMID: 24753986
PET/MRI; oncologic imaging; attenuation correction; ovarian cancer
12.  Positron emission tomography in the follow-up of cutaneous malignant melanoma patients: a systematic review 
Cutaneous malignant melanoma (CMM) has a high risk of dissemination to regional lymph nodes and visceral organs. Recurrences are most frequently seen within the first 2-3 years after initial treatment, but these patients have a life-long risk of relapse. The prognosis is highly dependent on lymph node involvement and distant metastases, accentuating the importance of close surveillance to identify disease progression at an early stage, and thereby detect recurrences amenable to treatment. Positron emission tomography (PET) has already been proven useful in the staging of CMM, but the utility of PET in follow-up programs for asymptomatic patients in high risk of relapse to detect systemic recurrences has yet to be investigated. We performed a systematic literature search in PUBMED, EMBASE and the Cochrane Controlled Trials Register, and identified 7 original studies on the diagnostic value of FDG-PET in the follow-up of CMM. Sensitivity, specificity, positive and negative predictive values were calculated to examine PET’s diagnostic value in detecting relapse. The mean sensitivity of PET was 96% and the specificity was 92%. The positive and negative predictive values were, respectively, 92% and 95%. Overall, PET has a high diagnostic value and the many advantages of PET indicate utility in the routine follow-up program of CMM. However, the number of prospective studies of high quality is scarce, and as the use of PET and PET/CT is becoming more widespread and the technology is expensive, there is an urgent need for systematic assessment of the diagnostic value.
PMCID: PMC3867726  PMID: 24380042
Melanoma; follow-up; PET; PET/CT; cancer; diagnostics; skin cancer; FDG
13.  PET radiopharmaceuticals for probing enzymes in the brain 
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.
PMCID: PMC3627518  PMID: 23638333
Positron emission tomography; monoamines; second messengers; kinase inhibitors; esterases
14.  Intravascular near-infrared fluorescence molecular imaging of atherosclerosis 
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.
PMCID: PMC3627519  PMID: 23638334
Near-infrared intravascular imaging; atherosclerosis; coronary; vulnerable plaque; inflammation; coronary stenting
15.  Stem cell tracking with optically active nanoparticles 
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.
PMCID: PMC3627520  PMID: 23638335
Stem cell therapy; optical imaging; nanoparticles; fluorescence imaging; photoacoustic imaging; Raman and surface enhanced Raman spectroscopy imaging
16.  EATRIS, a European initiative to boost translational biomedical research 
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.
PMCID: PMC3601476  PMID: 23526583
Drug development; european advanced translational research infrastructure (EATRIS); immuno-positron emission tomography; molecular imaging; personalized medicine; tyrosine kinase inhibitor-positron emission tomography; translational research
17.  Optical imaging of tumor microenvironment 
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.
PMCID: PMC3545362  PMID: 23342297
Optical imaging; tumor microenvironment; pH; hypoxia; protease
18.  Radiolabelled probes for imaging of atherosclerotic plaques 
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.
PMCID: PMC3484420  PMID: 23145360
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
19.  Non-invasive imaging of PI3K/Akt/mTOR signalling in cancer 
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.
PMCID: PMC3484421  PMID: 23145359
PI3K signalling; platinum based chemoresistance; repetitive and non-invasive molecular imaging techniques; PET imaging; bioluminescence imaging; Akt sensor; fluorescence imaging
20.  PET/MR in oncology: an introduction with focus on MR and future perspectives for hybrid 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.
PMCID: PMC3484424  PMID: 23145362
PET/MR; oncology; diagnosis; staging; therapy evaluation; radiotherapy planning; molecular imaging
21.  Altered sympathetic nervous system signaling in the diabetic heart: emerging targets for 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.
PMCID: PMC3477737  PMID: 23133819
Sympathetic neuronal imaging; SNS signaling; norepinephrine; β-adrenoceptor; norepinephrine reuptake transporter
22.  False-positive uptake on radioiodine whole-body scintigraphy: physiologic and pathologic variants unrelated to thyroid cancer 
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.
PMCID: PMC3477738  PMID: 23133823
Differentiated thyroid cancer; radioiodine; I-131; I-123; whole-body scintigraphy; false-positive; physiologic uptake; pathologic uptake
23.  Current neuroimaging techniques in Alzheimer's disease and applications in animal models 
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.
PMCID: PMC3477739  PMID: 23133824
Alzheimer’s disease; animal models; ASL; biomarkers; MRI; MRS; neuroimaging; PET
24.  Cerenkov imaging - a new modality for molecular imaging 
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.
PMCID: PMC3477724  PMID: 23133811
Cerenkov radiation; PET; optical imaging; fluorescence
25.  Current imaging strategies in rheumatoid arthritis 
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.
PMCID: PMC3477730  PMID: 23133812
Molecular imaging; magnetic resonance imaging; nuclear imaging; rheumatoid arthritis

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