Functional genomics and radioisotope-based imaging procedures

After the sequencing of the human genome has been completed, non-invasive imaging studies are needed to assess the function of new genes in living organisms. The evaluation of genetically manipulated animals or new designed biomolecules will require a thorough understanding of physiology, biochemistry and pharmacology, and the experimental approaches will involve many new technologies including in vivo imaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET). Nuclear medicine procedures may be applied for the determination of gene function and regulation using established and new tracers or using in vivo reporter genes such as enzymes, receptors, antigens or transporters. Pharmacogenomics will identify new surrogate markers for therapy monitoring which may represent potential new tracers for imaging. Also, drug distribution studies for new therapeutic biomolecules are needed at least during preclinical stages of drug development. Clinical gene therapy needs non-invasive tools to evaluate the efficiency of gene transfer. These informations can be used for therapy planning, follow-up studies in treated tumors and as an indicator of prognosis. Therapy planning is performed by the assessment of gene expression for example using radio-labeled specific substrates to determine the activity of suicide enzymes such as the Herpes Simplex Virus thymidine kinase. Follow-up studies with single photon emission tomography or positron emission tomography may be done to evaluate early or late effects of gene therapy on tumor metabolism or proliferation. Finally, new biomolecules will be developed by bioengineering methods which may be used for isotope-based diagnosis and treatment of disease.     

Cardiac Positron Emission Tomography: a Clinical Perspective

Cardiac positron emission tomography is a powerful, quantitative, non-invasive imaging modality, which adds valuable diagnostic and prognostic information to the clinical work-up. Myocardial perfusion and viability imaging are, as a result of continuously growing evidence, established clinical indications that may be cost-effective, due to the high diagnostic accuracy of cardiac positron emission tomography, despite high single-test costs. In the field of inflammation imaging, new indications are entering the clinical arena, which may contribute to a better diagnosis and overall patient care, as for instance in patients with cardiac sarcoidosis, prosthetic valve endocarditis and cardiac device infections. This review will discuss the individual strengths and weaknesses of cardiac positron emission tomography and, hence, the resulting clinical usefulness based on the current evidence for an individualized, patient-centered imaging approach.     

Non-invasive Imaging in Gene Therapy.

Several methods are available for non-invasive imaging of gene delivery and transgene expression, including magnetic resonance imaging (MRI), single photon emission tomography (SPECT)/positron emission tomography (PET), and fluorescence and bioluminescence imaging. However, these imaging modalities differ greatly in terms of their sensitivity, cost, and ability to measure the signal. Whereas MRI can produce a resolution of approximately 50 mum, optical imaging achieves only 3-5 mm but outperforms MRI in terms of the cost of the imaging device. Similarly, SPECT and PET give a resolution of only 1-2 mm but provide for relatively easy quantitation of the signal and need only nanograms of probe, compared with the microgram or milligram levels required for MRI and optical imaging. To develop safer and more efficient gene delivery vectors, it is essential to perform rigorous in vivo experiments, to image particle biodistribution and transduction patterns, and to quantify the transgene expression profile. Differences between modalities have a significant effect on the resultant imaging resolution for gene therapy. This review describes the methodologies in use and highlights recent key approaches using the latest imaging modalities in gene therapy. Future trends in gene therapy imaging are also discussed.     

Radiohalogenated nonnatural amino acids as PET and SPECT tumor imaging agents

Radiohalogenated α-amino acids are a diverse and useful class tumor imaging agents suitable for positron emission tomography and single photon emission computed tomography. These tracers target the increased rates of amino acid transport exhibited by many tumor cells. The most established clinical use for radiolabeled amino acids is imaging primary and recurrent gliomas, and there is growing evidence that they may also be useful for other oncologic applications, including neuroendocrine tumors and prostate cancer. This review focuses on the synthesis, radiolabeling, and preclinical evaluation of three series of nonnatural radiohalogenated amino acids: alicyclic, α,α-dialkyl, and 1H-[1,2,3]triazole amino acids which target system L, system A, and cationic amino acid transport systems, respectively.     

Current and Future Status of Blood Flow Tracers

Myocardial perfusion imaging is important for the management of patients with suspected or known coronary artery disease. Nuclear cardiology is the most widely used noninvasive approach for the assessment of myocardial perfusion. The available single-photon emission CT (SPECT) flow agents are characterized by a rapid myocardial extraction and by a cardiac uptake proportional to blood flow. In addition, different positron emission tomography (PET) tracers may be used for the absolute quantitative measurement of myocardial blood flow and coronary flow reserve. However, the available SPECT and PET tracers for myocardial perfusion imaging have some limitations that must be considered to maximize their clinical applications and there is still a well-recognized need for the development of new perfusion tracers with more ideal properties. This review illustrates the current status and the future perspectives of blood flow tracers for SPECT and PET myocardial perfusion imaging.     

The clinical value of cardiac sympathetic imaging in heart failure

The autonomic nervous system plays an important role in the pathology of heart failure. The single‐photon emission computed tomography tracer iodine‐123‐metaiodobenzylguanidine (¹²³I‐MIBG) can be used to investigate the activity of the predominant neurotransmitter of the sympathetic nervous system, norepinephrine. Also, positron emission tomography tracers are being developed for the same purpose. With ¹²³I‐MIBG as a starting point, this brief review introduces the modalities used for cardiac sympathetic imaging.     

Cardiac Imaging as a Guide for Revascularization and Medical Management of Chronic Coronary Artery Disease

There is a strong association between obstructive coronary artery disease (CAD) and adverse outcomes. There is an ongoing debate regarding the role of revascularization and maximal medical therapy in patients with obstructive CAD and noninvasive imaging is recognized as a key player in guiding downstream clinical decision making especially in stable patients with known or suspected CAD. Most often risk stratification is performed with noninvasive imaging techniques including echocardiography, coronary CT angiography, single photon emission computed tomography myocardial perfusion imaging (SPECT-MPI), positron emission computed tomography-based myocardial perfusion imaging (PET-MPI), and magnetic resonance imaging (MRI). Occasionally, risk stratification may be performed with invasive angiography. In this review, we will describe some of the evidence in favor of noninvasive anatomy (CCTA) and physiology-based techniques (SPECT-MPI, PET-MPI, MRI) in guiding the choice of treatment with revascularization vs medical therapy in patients with CAD.     

Role of nuclear cardiology for guiding device therapy in patients with heart failure

Heart failure is a dynamic condition with high morbidity and mortality and its prognosis should be reassessed frequently, particularly in patients for whom critical treatment decisions may depend on the results of prognostication. In patients with heart failure, nuclear cardiology techniques are useful to establish the etiology and the severity of the disease, while fewer studies have explored the potential capability of nuclear cardiology to guide cardiac resynchronization therapy(CRT) and to select patients for implantable cardioverter defibrillators(ICD). Left ventricular synchrony may be assessed by radionuclide angiography or gated singlephoton emission computed tomography myocardial perfusion scintigraphy. These modalities have shown promise as predictors of CRT outcome using phase analysis. Combined assessment of myocardial viability and left ventricular dyssynchrony is feasible using positron emission tomography and could improve conventional response prediction criteria for CRT. Preliminary data also exists on integrated positron emission tomography/computed tomography approach for assessing myocardial viability, identifying the location of biventricular pacemaker leads, and obtaining left ventricular functional data, including contractile phase analysis. Finally, cardiac imaging with autonomic radiotracers may be useful in predicting CRT response and for identifying patients at risk for sudden cardiac death, therefore potentially offering a way to select patients for both CRT and ICD therapy. Prospective trials where imaging is combined with image-test driven therapy are needed to better define the role of nuclear cardiology for guiding device therapy in patients with heart failure.     

BMIPP imaging to assess functional outcome in patients with acute and chronic left ventricular dysfunction

Assessment of myocardial viability is an important clinical issue for patient management during the acute and chronic stages of myocardial infarction. BMIPP (15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid) is a free fatty acid analogue which is trapped in the myocardium, thus permitting for metabolic imaging with single photon emission computerized tomography (SPECT). Less BMIPP than flow tracers that may be observed in the areas of infarction, may reflect the metabolic shift from fatty acid to glucose utilization in ischaemic myocardium. In this sense, the combined imaging of BMIPP and a flow tracer with SPECT may provide similar and important information as fluoro-18 deoxyglucose (FDG) and positron emission tomography (PET) regarding the assessment of myocardial viability. The purpose of this article is to review the clinical impact of BMIPP in patients with acute and with chronic left ventricular dysfunction for the identification of jeopardized but viable myocardium and the prediction of the functional outcome.     

Expansion of the lymphatic vasculature in cancer and inflammation: New opportunities for in vivo imaging and drug delivery

Over the last 15 years, discovery of key growth factors and specific molecular markers for lymphatic vessels has enabled a new era of molecular research on the lymphatic vascular system. As a result, it has been found that lymphangiogenesis, the expansion of existing lymphatic vessels, plays an important role in tumor progression and in the control of chronic inflammation. At the same time, technical advancements have been made to improve the visualization of the lymphatic system. We have recently developed liposomal and polymer-based formulations of near-infrared lymphatic-specific imaging tracers for the non-invasive quantitative in vivo imaging of lymphatic vessel function. Using these tracers, a near-infrared stereomicroscope system allows imaging of initial and collecting lymphatic vessels with high spatial and temporal resolution in mice. In addition, we have developed a new method, using antibodies to a lymphatic specific marker and positron emission tomography, to sensitively detect lymphatic expansion in lymph nodes as the earliest sign of cancer metastasis. These imaging methods have great potential to provide non-invasive measures to assess the functionality of the lymphatic system and to assess the efficiency of lymphatic drug delivery.     

Sortase A‐mediated site‐specific labeling of camelid single‐domain antibody‐fragments: a versatile strategy for multiple molecular imaging modalities

A generic site‐specific conjugation method that generates a homogeneous product is of utmost importance in tracer development for molecular imaging and therapy. We explored the protein‐ligation capacity of the enzyme Sortase A to label camelid single‐domain antibody‐fragments, also known as nanobodies. The versatility of the approach was demonstrated by conjugating independently three different imaging probes: the chelating agents CHX‐A"‐DTPA and NOTA for single‐photon emission computed tomography (SPECT) with indium‐111 and positron emission tomography (PET) with gallium‐68, respectively, and the fluorescent dye Cy5 for fluorescence reflectance imaging (FRI). After a straightforward purification process, homogeneous single‐conjugated tracer populations were obtained in high yield (30–50%). The enzymatic conjugation did not affect the affinity of the tracers, nor the radiolabeling efficiency or spectral characteristics. In vivo, the tracers enabled the visualization of human epidermal growth factor receptor 2 (HER2) expressing BT474M1‐tumors with high contrast and specificity as soon as 1 h post injection in all three imaging modalities. These data demonstrate Sortase A‐mediated conjugation as a valuable strategy for the development of site‐specifically labeled camelid single‐domain antibody‐fragments for use in multiple molecular imaging modalities. Copyright © 2016 John Wiley & Sons, Ltd.     

Myocardial perfusion imaging to evaluate the efficacy of medical therapy in patients with coronary artery disease

Myocardial perfusion imaging is commonly used to risk-stratify patients based on the presence and extent of stress-induced myocardial ischemia. Recent studies have shown that both positron and single photon emission tomography techniques can be used to assess the effectiveness of coronary revascularization procedures as well as various anti-ischemic medical therapies on myocardial perfusion. In this regard, perfusion imaging may be used not only to assess initial risk but also to track subsequent risk based on changes in perfusion results following medical and/or interventional therapies.     

Urokinase‐type plasminogen activator receptor (uPAR) as a promising new imaging target: potential clinical applications

Urokinase‐type plasminogen activator receptor (uPAR) has been shown to be of special importance during cancer invasion and metastasis. However, currently, tissue samples are needed for measurement of uPAR expression limiting the potential as a clinical routine. Therefore, non‐invasive methods are needed. In line with this, uPAR has recently been identified as a very promising imaging target candidate. uPAR consists of three domains attached to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor and binds it natural ligand uPA with high affinity to localize plasminogen activation at the cell surface. Due to the importance of uPAR in cancer invasion and metastasis, a number of high‐affinity ligands have been identified during the last decades. These ligands have recently been used as starting point for the development of a number of ligands for imaging of uPAR using various imaging modalities such as optical imaging, magnetic resonance imaging, single photon emission computer tomography (SPECT) and positron emission topography (PET). In this review, we will discuss recent advances in the development of uPAR‐targeted imaging ligands according to imaging modality. In addition, we will discuss the potential future clinical application for uPAR imaging as a new imaging biomarker.     

Combined I-124 Positron Emission Tomography/Computed Tomography Imaging of NIS Gene Expression in Animal Models of Stably Transfected and Intravenously Transfected Tumor

Purpose With the advent of replication competent viruses for cancer gene therapy, it has become imperative to monitor the biodistribution, expression and replication of these vectors in living organisms. We evaluated the potential of I-124 positron emission tomography (PET)/computed tomography (CT) imaging in gene therapy animal models utilizing the sodium iodide symporter (NIS) and compared the findings to I-123 gamma camera imaging. Procedures CB17 SCID mice were implanted with myeloma cell lines expressing NIS or infected by MV-NIS given systemically. Mice were imaged by both gamma camera (I-123) and PET/CT (I-124 ) and image quality assessed. Results NIS expressing tumors concentrated 7.1% of the injected activity while tumors infected with the control virus had only 0.3% of the activity injected. Conclusions I-124 PET/CT in combination with NIS allows the tracking of stably transfected tumors or intravenously transfected tumors. Combined modality imaging using PET/CT allows accurate and non-invasive imaging of the distribution and gene expression of a replicating viral vector in living systems.     

Review: comparison of PET rubidium‐82 with conventional SPECT myocardial perfusion imaging

Nuclear cardiology has for many years been focused on gamma camera technology. With ever improving cameras and software applications, this modality has developed into an important assessment tool for ischaemic heart disease. However, the development of new perfusion tracers has been scarce. While cardiac positron emission tomography (PET) so far largely has been limited to centres with on‐site cyclotron, recent developments with generator produced perfusion tracers such as rubidium‐82, as well as an increasing number of PET scanners installed, may enable a larger patient flow that may supersede that of gamma camera myocardial perfusion imaging.     

Application of MR/PET in Oncologic Imaging

The present review aims to depict the possibilities offered by hybrid imaging with magnetic resonance positron emission tomography (MR/PET). Recently, new whole-body MR/PET scanners were introduced allowing for the combination of both modalities outside the brain. This is a challenge for both modalities: For MRI, it is essential to provide anatomical images with high resolution. Additionally, diffusion-weighted imaging (DWI), proton spectroscopy, but also dynamic contrast-enhanced imaging plays an important role. With regard to PET, the technical challenge mainly consists of obtaining an appropriate MR-based attenuation correction for the PET data. Using MR/PET, it is possible to acquire morphological and functional data in one examination. In particular, children and young adults will benefit from this new hybrid technique, especially in oncologic imaging with multiple follow-up examinations. However, it is expected that PET/CT will not be replaced completely by MR/PET because PET/CT is less cost-intensive and more widely available. Moreover, in lung imaging, MRI limitations still have to be accepted. Concerning research, simultaneous MR/PET offers a variety of new possibilities, for example cardiac imaging, functional brain studies or the evaluation of new tracers in correlation with specific MR techniques.     

中枢神经系统对排尿的控制和调节

排尿是一项复杂的生理活动,受多级神经的控制。随着正电子发射断层扫描单光子发射计算机断层扫描以及功能磁共振成像技术的应用,人们可以在膀胱储尿和排尿的同时进行脑功能实时成像。本文针对排尿的生理、中枢的调控进行综述。     

Molecular Imaging of Left Ventricular Remodeling

Every year nearly 1 million Americans with myocardial infarction suffer from acute coronary syndromes. Despite advances in reperfusion therapy, these molecular events may often lead to ventricular adverse remodeling resulting in the heart failure. This observation became a driving force to develop noninvasive imaging strategies to evaluate remodeling using concepts of molecular imaging. As such, cardiovascular imaging plays an important role in shifting the paradigm from the disease treatment to early diagnosis, prognostication, and stratification, which has a tremendous potential to alleviate socioeconomic and health care costs associated with the treatment of heart failure patients. This review is intended to be a brief overview of recent nuclear imaging techniques and applications to assess molecular events associated with the process of left ventricular (LV) remodeling following myocardial infarction (MI). The specific approaches presented here will include imaging of perfusion, viability, metabolism, cardiac neuroreceptors, angiogenesis, proteases activity, and renin-angiotensin-aldosterone system activation. We will first describe basic concepts of molecular imaging, then we will provide an overview of recent advances in molecular imaging technology, and finally we will report current nuclear imaging strategies in assessment of LV remodeling. The emphasis will be put on radiotracer-based modalities including single photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques, although other clinical imaging modalities will be also briefly discussed. We expect that in near future these targeted imaging approaches will complement standard physiological parameters and will play a crucial role in post-MI patients’ stratification and development of individual therapy regimes.     

Weaving Single Photon Imaging into New Drug Development

The specific aim of this review is to assess the potential contribution of single photon emitting radiopharmaceutical technologies to new drug development. For each phase of therapeutic drug development, published literature was sought that shows single photon emitters can add value by quantifying pharmacokinetics, visualizing mechanisms of drug action, estimating therapeutic safety indices, or measuring dose-dependent pharmacodynamic effects. Not any published reports were found that describe using nuclear medicine techniques to help manage the progress of a new drug development program. As a consequence, most of the case in favor of weaving single photon imaging into the process had to be built on extrapolations from studies that showed feasibility post hoc. The strongest evidence of potential value was found for drug candidates that hope to influence diseases characterized by cell proliferation or cell death, particularly in the fields of oncology, cardiology, nephrology, and inflammation. Receptor occupancy studies were observed to occasionally offer unique advantages over analogous studies with positron emission tomography (PET). Enough hard data sets were found to justify the costs of using single photon imaging in a variety of new drug development paradigms.