Emerging Tracers for Nuclear Cardiac PET Imaging

Myocardial perfusion imaging using positron emission tomography (PET) has several advantages over single photon emission computed tomography (SPECT). The recent advances in SPECT technology have shown promise, but there is still a large need for PET in the clinical management of coronary artery disease (CAD). Especially, absolute quantification of myocardial blood flow (MBF) using PET is extremely important. In spite of considerable advances in the diagnosis of CAD, novel PET radiopharmaceuticals remain necessary for the diagnosis of CAD because clinical use of current cardiac radiotracers is limited by their physical characteristics, such as decay mode, emission energy, and half-life. Thus, the use of a radioisotope that has proper characteristics and a proper half-life to develop myocardial perfusion agents could overcome these limitations. In this review, the current state of cardiac PET and a general overview of novel ¹⁸F or ⁶⁸Ga-labeled radiotracers, including their radiosynthesis, in vivo characterization, and evaluation, are provided. The future perspectives are discussed in terms of their potential usefulness based on new image analysis methods and hybrid imaging.     

PET in cardiology

Myocardial perfusion imaging with single-photon emission CT (SPECT) is a key investigation in the work-up of patients with coronary artery disease. PET, however, with inherently better spatial and temporal resolution, offers several advantages over SPECT. The last decade has witnessed extensive application of PET techniques to assess myocardial viability and has provided valuable information important in analyzing the risk: benefit ratio for several therapeutic measures. Recent advances in PET instrumentation and radiopharmaceuticals have generated considerable interest to use PET for evaluating an array of cardiovascular disease.     

Molecular body imaging: MR imaging, CT, and US. part I. principles

Molecular imaging, generally defined as noninvasive imaging of cellular and subcellular events, has gained tremendous depth and breadth as a research and clinical discipline in recent years. The coalescence of major advances in engineering, molecular biology, chemistry, immunology, and genetics has fueled multi- and interdisciplinary innovations with the goal of driving clinical noninvasive imaging strategies that will ultimately allow disease identification, risk stratification, and monitoring of therapy effects with unparalleled sensitivity and specificity. Techniques that allow imaging of molecular and cellular events facilitate and go hand in hand with the development of molecular therapies, offering promise for successfully combining imaging with therapy. While traditionally nuclear medicine imaging techniques, in particular positron emission tomography (PET), PET combined with computed tomography (CT), and single photon emission computed tomography, have been the molecular imaging methods most familiar to clinicians, great advances have recently been made in developing imaging techniques that utilize magnetic resonance (MR), optical, CT, and ultrasonographic (US) imaging. In the first part of this review series, we present an overview of the principles of MR imaging-, CT-, and US-based molecular imaging strategies.     

Positron emission tomography and single-photon emission computed tomography in substance abuse research

Many advances in the conceptualization of addiction as a disease of the brain have come from the application of imaging technologies directly in the human drug abuser. New knowledge has been driven by advances in radiotracer design and chemistry and positron emission tomography (PET) and single-photon emission computed tomography (SPECT) instrumentation and the integration of these scientific tools with the tools of biochemistry, pharmacology, and medicine. This topic cuts across the medical specialties of neurology, psychiatry, oncology, and cardiology because of the high medical, social, and economic toll that drugs of abuse, including the legal drugs, cigarettes and alcohol, take on society. This article highlights recent advances in the use of PET and SPECT imaging to measure the pharmacokinetic and pharmacodynamic effects of drugs of abuse on the human brain.     

Nuklearmedizinische Diagnostik bei Erkrankungen des zentralen Nervensystems

Positron-emission tomography (PET) and single photon emission computed tomography (SPECT) can be used to visualize and quantify cerebral perfusion, glucose consumption, neurotransmission, and amino acid uptake. These techniques are clearly superior to conventional structural imaging techniques for several indications. This contribution describes the clinical role of PET and SPECT in clinical neurology.     

SPECT and PET imaging in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Beta-amyloid (Aβ) deposition and neurofibrillary tangles (NFTs) of abnormal hyperphosphorylated tau protein are the pathological hallmarks of the disease, accompanied by other pathological processes such as microglia activation. Functional and molecular nuclear medicine imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques provides valuable information about the underlying pathological processes, many years before the appearance of clinical symptoms. Nuclear neuroimaging in AD has made great progress in the past two decades and has extended beyond the traditional role of brain perfusion and glucose metabolism evaluation. Intense efforts in radiopharmaceuticals research have led to the development of various probes able to detect Aβ deposits, tau protein accumulation, microglia activation and neuroinflammation. As a result, SPECT and PET have proposed to serve as biomarkers in recently revised diagnostic clinical criteria for the early diagnosis of AD and the prediction of progression to AD in mild cognitive impairment (MCI) subjects.     

PET versus SPECT: strengths, limitations and challenges

The recent introduction of high-resolution molecular imaging technology is considered by many experts as a major breakthrough that will potentially lead to a revolutionary paradigm shift in health care and revolutionize clinical practice. This paper intends to balance the capabilities of the two major molecular imaging modalities used in nuclear medicine, namely positron emission tomography (PET) and single photon emission computed tomography (SPECT). The motivations are many-fold: (1) to gain a better understanding of the strengths and limitations of the two imaging modalities in the context of recent and ongoing developments in hardware and software design; (2) to emphasize that certain issues, historically and commonly thought as limitations of one technology, may now instead be viewed as challenges that can be addressed; (3) to point out that current state of the art PET and SPECT scanners can (greatly) benefit from improvements in innovative image reconstruction algorithms; and (4) to identify important areas of research in PET and SPECT imaging that will be instrumental to further improvements in the two modalities. Both technologies are poised to advance molecular imaging and have a direct impact on clinical and research practice to influence the future of molecular medicine.     

Taking the perfect nuclear image: Quality control, acquisition, and processing techniques for cardiac SPECT, PET, and hybrid imaging

Nuclear Cardiology for the past 40 years has distinguished itself in its ability to non-invasively assess regional myocardial blood flow and identify obstructive coronary disease. This has led to advances in managing the diagnosis, risk stratification, and prognostic assessment of cardiac patients. These advances have all been predicated on the collection of high quality nuclear image data. National and international professional societies have established guidelines for nuclear laboratories to maintain high quality nuclear cardiology services. In addition, laboratory accreditation has further advanced the goal of the establishing high quality standards for the provision of nuclear cardiology services. This article summarizes the principles of nuclear cardiology single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging and techniques for maintaining quality: from the calibration of imaging equipment to post processing techniques. It also will explore the quality considerations of newer technologies such as cadmium zinc telleride (CZT)-based SPECT systems and absolute blood flow measurement techniques using PET.     

Imaging with F-18 FDG PET is superior to Tl-201 SPECT in the staging of non-small cell lung cancer for radical radiation therapy

Thallium-201 (Tl-201) single photon emission computed tomography (SPECT) is funded for evaluation of malignancy in Australia and may have utility for staging of non-small cell lung cancer (NSCLC) if CT results are equivocal. Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) is superior to CT for staging NSCLC but is more expensive and less widely available than Tl-201 SPECT. Therefore, these techniques were prospectively compared in 27 radical radiation therapy candidates. Patients were allocated a conventional, PET and Tl-201 stage. Tumour to background ratios (TBR) were recorded for the primary on both techniques. Metastatic disease was confirmed by surgical pathology, serial imaging or clinical follow up. Tumour to background ratios were consistently higher for FDG PET than Tl-201 SPECT (P < 0.0001). Positron emission tomography detected all known primary tumours but Tl-201 failed to image four primary tumours (15%). In 10 of 18 cases of discordance between PET and Tl-201 SPECT regarding stage, corroboration was available from pathology or disease progression. Positron emission tomography was shown to have a 100% positive predictive value, including all three patients with PET-detected distant metastases (P=0.002). Results indicate that PET is superior to Tl-201 SPECT scanning in the staging of NSCLC for radical radiation therapy, and that the low sensitivity for detection of local and metastatic disease is likely to limit the clinical impact and cost-effectiveness of this technique despite its lower cost.     

Establishment of Animal Models with Orthotopic Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most serious health problems worldwide. Many researchers have investigated HCC at the level of genes, ribonucleic acid, proteins, cells, and animals. The resultant development of animal models and monitoring methods has improved the effectiveness of guidelines provided to researchers working with preclinical HCC models. HCC in animal models and clinical patients is monitored by various current imaging modalities such as ultrasound (US) imaging, computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET) and bioluminescence imaging (BLI). These techniques are currently used for both preclinical and clinical assessment, and provide valuable diagnostic information. In this article, we have mainly reviewed the established animal models and the assessment of orthotopic HCC using imaging modalities. Additionally, we have introduced a method of orthotopic HCC rat model developed in our laboratory. We have furthermore evaluated the occurrence of tumor mass using molecular imaging techniques.     

New horizons in cardiac innervation imaging: introduction of novel <Superscript>18</Superscript>F-labeled PET tracers

Cardiac sympathetic nervous activity can be uniquely visualized by non-invasive radionuclide imaging techniques due to the fast growing and widespread application of nuclear cardiology in the last few years. The norepinephrine analogue ¹²³I–meta-iodobenzylguanidine (¹²³I–MIBG) is a single photon emission computed tomography (SPECT) tracer for the clinical implementation of sympathetic nervous imaging for both diagnosis and prognosis of heart failure. Meanwhile, positron emission tomography (PET) imaging has become increasingly attractive because of its higher spatial and temporal resolution compared to SPECT, which allows regional functional and dynamic kinetic analysis. Nevertheless, wider use of cardiac sympathetic nervous PET imaging is still limited mainly due to the demand of costly on-site cyclotrons, which are required for the production of conventional ¹¹C-labeled (radiological half-life, 20 min) PET tracers. Most recently, more promising ¹⁸F-labeled (half-life, 110 min) PET radiopharmaceuticals targeting sympathetic nervous system have been introduced. These tracers optimize PET imaging and, by using delivery networks, cost less to produce. In this article, the latest advances of sympathetic nervous imaging using ¹⁸F-labeled radiotracers along with their possible applications are reviewed.     

Single-photon emission computed tomography/computed tomography in brain tumors

Anatomic imaging procedures (computed tomography [CT] and magnetic resonance imaging [MRI]) have become essential tools for brain tumor assessment. Functional images (positron emission tomography [PET] and single-photon emission computed tomography [SPECT]) can provide additional information useful during the diagnostic workup to determine the degree of malignancy and as a substitute or guide for biopsy. After surgery and/or radiotherapy, nuclear medicine examinations are essential to assess persistence of tumor, to differentiate recurrence from radiation necrosis and gliosis, and to monitor the disease. The combination of functional images with anatomic ones is of the utmost importance for a full evaluation of these patients, which can be obtained by means of imaging fusion. Despite the fast-growing diffusion of PET, in most cases of brain tumors, SPECT studies are adequate and provide results that parallel those obtained with PET. The main limitation of SPECT imaging with brain tumor-seeking radiopharmaceuticals is the lack of precise anatomic details; this drawback is overcome by the fusion with morphological studies that provide an anatomic map to scintigraphic data. In the past, software-based fusion of independently performed SPECT and CT or MRI demonstrated usefulness for brain tumor assessment, but this process is often time consuming and not practical for everyday nuclear medicine studies. The recent development of dual-modality integrated imaging systems, which allow the acquisition of SPECT and CT images in the same scanning session, and their co-registration by means of the hardware, has facilitated this process. In SPECT studies of brain tumors with various radiopharmaceuticals, fused images are helpful in providing the precise localization of neoplastic lesions, and in excluding the disease in sites of physiologic tracer uptake. This information is useful for optimizing diagnosis, therapy monitoring, and radiotherapy treatment planning, with a positive impact on patient management.     

Functional brain imaging in the evaluation of psychiatric illness

In the past century, the field of psychiatry has undergone major changes. During this time, significant advancements in both diagnosis and treatment have occurred. Medical brain imaging using structural and functional brain imaging techniques have contributed, in part, to a better basic understanding of psychiatric disease and to an improving diagnostic approach. Computed tomography and magnetic resonance imaging have supplied limited, but useful insight regarding structural alterations in schizophrenia and the affective disorders. Position emission tomography imaging has already made a major contribution in the assessment of schizophrenia and affective disorders. Single-photon emission computed tomography (SPECT), which is currently more widely available, should contribute more to psychiatric disease evaluation in the future. Recent advances in SPECT technology in the areas of improved instrumentation--such as multidetector and ring detector systems and new radiopharmaceuticals including new rCBF markers and receptor site imaging agents--have contributed to significant improvements in the SPECT imaging technique. At the present time, SPECT has been shown to be feasible and useful in the evaluation of acute and chronic psychiatric and demented states. As SPECT technology continues to evolve, further refinements in this diagnostic capability can be anticipated.     

Molecular imaging of gene expression and protein function in vivo with PET and SPECT

Molecular imaging is broadly defined as the characterization and measurement of biological processes in living animals, model systems, and humans at the cellular and molecular level using remote imaging detectors. One underlying premise of molecular imaging is that this emerging field is not defined by the imaging technologies that underpin acquisition of the final image per se, but rather is driven by the underlying biological questions. In practice, the choice of imaging modality and probe is usually reduced to choosing between high spatial resolution and high sensitivity to address a given biological system. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) inherently use image-enhancing agents (radiopharmaceuticals) that are synthesized at sufficiently high specific activity to enable use of tracer concentrations of the compound (picomolar to nanomolar) for detecting molecular signals while providing the desired levels of image contrast. The tracer technologies strategically provide high sensitivity for imaging small-capacity molecular systems in vivo (receptors, enzymes, transporters) at a cost of lower spatial resolution than other technologies. We review several significant PET and SPECT advances in imaging receptors (somatostatin receptor subtypes, neurotensin receptor subtypes, alpha(v)beta(3) integrin), enzymes (hexokinase, thymidine kinase), transporters (MDR1 P-glycoprotein, sodium-iodide symporter), and permeation peptides (human immunodeficiency virus type 1 (HIV-1) Tat conjugates), as well as innovative reporter gene constructs (herpes simplex virus 1 thymidine kinase, somatostatin receptor subtype 2, cytosine deaminase) for imaging gene promoter activation and repression, signal transduction pathways, and protein-protein interactions in vivo.     

Evolution of brain imaging instrumentation

Computed tomography (CT) and static magnetic resonance imaging (MRI) are now the most common imaging modalities used for anatomic evaluation of pathologic processes affecting the brain. By contrast, radionuclide-based methods, including planar imaging, single-photon emission computed tomography (SPECT), and positron emission tomography (PET), are the most widely used methods for evaluating brain function. SPECT and PET have been evolving for a longer time than CT and MRI and have made significant contributions to understanding brain function. The pioneering work on cerebral flow early in the last century laid the foundation of measurement with radioactive gases. This was initially performed with scintillation counters, which gave way to single, then multiple scintillation and multiprobe detectors. The invention of rectilinear scanners, MARK series, Anger cameras, and SPECT imaging further advanced nuclear medicine's role in brain imaging. Measurement of regional cerebral blood flow by SPECT provides pathophysiologic information that directs patient management in a variety of central nervous disorders (CNS), with the greatest clinical impact found in cerebrovascular disease and seizure disorder. In the former, SPECT not only provides means of early detection and localization of acute strokes but can also direct thrombolysis and determine prognosis in the postcerebrovascular accident period. With respect to the latter, ictal SPECT can localize seizure foci so that patients with refractory disease can potentially undergo surgical resection of the affected area. In contrast to brain SPECT, brain PET images reflect regional cerebral metabolism. Because of neurovascular coupling, findings on SPECT and PET images are often comparable. PET, however, still has improved spatial resolution and is therefore more sensitive than SPECT, particularly in the evaluation of dementias. Brain PET instrumentation has greatly evolved from its infancy, when it was used in regional localization, to currently providing excellent resolution with imaging characteristics that can greatly impact clinical management. In addition, although ictal SPECT remains more sensitive than interictal PET for detection of seizure foci, the stringent conditions required for SPECT can be difficult to achieve, making interictal PET a very reasonable alternative. The clinical utility of PET and SPECT in neuropsychiatric and addictive disorders has not yet been defined, though a plethora of data exits. This arena of CNS disease has been the impetus for development of neurotransmitter-receptor-specific radioligands, which have already led to better understanding of dopaminergic, GABAergic, and serotonergic pathways. Another functional brain imaging technique that has gained broad acceptance since its invention in the early 1990 s, is functional MRI, which indirectly measures CNS neuronal activity by evaluating oxygenation levels of cerebral vessels. Despite other recent related developments, such as MR spectroscopy, arterial spin labeling, and diffusion tensor imaging, nuclear medicine-based techniques remain clinically relevant and robust modalities, especially with the ever-expanding armamentarium of radiotracers and radioligands in conjunction with industry-driven improvements in image-analysis hardware and software.     

Value and limitation of stress thallium-201 single photon emission computed tomography: comparison with nitrogen-13 ammonia positron tomography

The diagnostic value of exercise 201Tl single photon emission computed tomography (SPECT) for assessing coronary artery disease (CAD) was comparatively evaluated with exercise [13N] ammonia positron emission tomography (PET). Fifty-one patients underwent both stress-delayed SPECT imaging using a rotational gamma camera and stress-rest PET imaging using a high resolution PET camera. Of 48 CAD patients, SPECT showed abnormal perfusion in 46 patients (96%), while PET detected perfusion abnormalities in 47 (98%). The sensitivity for detecting disease in individual coronary arteries (greater than 50% stenosis) was also similar for SPECT (81%) and PET (88%). When their interpretations were classified as normal, transient defect, and fixed defect in 765 myocardial segments, SPECT and PET findings were concordant in 606 segments (79%). However, 66 segments showed a fixed defect by SPECT but a transient defect by PET, whereas there were only nine segments showing a transient defect by SPECT and a fixed defect by PET. PET identified transient defects in 34% of the myocardial segments showing a fixed defect by SPECT. We conclude that both stress SPECT and PET showed high and similar sensitivities for detecting CAD and individual stenosed vessels. Since stress-delayed SPECT with single tracer injection detected fewer transient defects, it may underestimate the presence of myocardial ischemia, compared with high resolution PET imaging with two tracer injections.     

Molekulare Bildgebung bei neurologischen Erkrankungen

In neurodegeneration and in neuro-oncology, the standard imaging procedure, magnetic resonance imaging (MRI), shows limited sensitivity and specificity. Molecular imaging with specific positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers allows various molecular targets and metabolic processes to be assessed and is thus a valuable adjunct to MRI. Two important examples are referred to here: amino acid transport for neuro-oncological issues, and the recently approved PET tracers for detecting amyloid depositions during the preclinical stage of Alzheimer’s disease. This review discusses the clinical relevance and indications for the following nuclear medicine imaging procedures: amyloid PET, ¹⁸F-fluorodeoxyglucose (FDG)-PET, and dopamine transporter (DaT)-SPECT for the diagnosis of dementia and the differential diagnosis of Parkinson’s disease, in addition to amino acid PET for the diagnosis of brain tumors and somatostatin receptor imaging in meningioma.     

The increasing role of quantification in clinical nuclear cardiology: The Emory approach

Single photon emission computed tomography (SPECT) myocardial perfusion imaging has attained widespread clinical acceptance as a standard of care for patients with known or suspected coronary artery disease. A significant contribution to this success has been the use of computer techniques to provide objective quantitative assessment in interpreting these studies. We have implemented the Emory Cardiac Toolbox (ECTb) as a pipeline to distribute the software tools that we and others have researched, developed, and validated to be clinically useful so that diagnosticians everywhere can benefit from our work. Our experience has demonstrated that integration of all software tools in a common platform is the optimal approach to promote both accuracy and efficiency. Important attributes of the ECTb approach are (1) our extensive number of normal perfusion databases for SPECT and positron emission tomography (PET) studies, each created with at least 150 patients: (2) our use of Fourier analysis of regional thickening to ensure proper temporal resolution and to allow accurate measurement of left ventricular function and dyssynchrony: (3) our development of PET tools to quantify myocardial hibernation and viability; (4) our development of 3-dimensional displays and the use of these displays as a platform for image fusion of perfusion and computed tomography angiography; and (5) the use of expert systems for decision support. ECTb is an important tool for extracting quantitative parameters from all types of cardiac radionuclide distributions. ECTb should continue to play an important role in establishing cardiac SPECT and PET for flow, function, metabolism, and innervation clinical applications.     

Nuclear medicine in pediatric neurology and neurosurgery: epilepsy and brain tumors

In pediatric drug-resistant epilepsy, nuclear medicine can provide important additional information in the presurgical localization of the epileptogenic focus. The main modalities used are interictal (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and ictal regional cerebral perfusion study with single-photon emission computed tomography (SPECT). Nuclear medicine techniques have a sensitivity of approximately 85% to 90% in the localization of an epileptogenic focus in temporal lobe epilepsy; however, in this clinical setting, they are not always clinically indicated because other techniques (eg, icterictal and ictal electroencephalogram, video telemetry, magnetic resonance imaging [MRI]) may be successful in the identification of the epileptogenic focus. Nuclear medicine is very useful when MRI is negative and/or when electroencephalogram and MRI are discordant. A good technique to identify the epileptogenic focus is especially needed in the setting of extra-temporal lobe epilepsy; however, in this context, identification of the epileptogenic focus is more difficult for all techniques and the sensitivity of the isotope techniques is only 50% to 60%. This review article discusses the clinical value of the different techniques in the clinical context; it also gives practical suggestions on how to acquire good ictal SPECT and interictal FDG-PET scans. Nuclear medicine in pediatric brain tumors can help in differentiating tumor recurrence from post-treatment sequelae, in assessing the response to treatment, in directing biopsy, and in planning therapy. Both PET and SPECT tracers can be used. In this review, we discuss the use of the different tracers available in this still very new, but promising, application of radioisotope techniques.     

The future of SPECT in a time of PET

As positron emission tomography (PET) imaging is becoming more prevalent in clinical practice, it is reasonable to ask if there will be a role for single photon emission computed tomography (SPECT) in the future. This article considers that question, focusing on areas where SPECT can differentiate itself from PET for fundamental reasons: breadth of available radionuclides, simultaneous imaging of multiple agents, cost-effectiveness and adaptability to specific imaging situations. The conclusion is that SPECT will continue to evolve and exist alongside PET and will grow the field of molecular imaging with improved efficiency and patient workflow.