Recent developments in 99Tcm-labelled peptide-based radiopharmaceuticals: an overview

Nature has designed peptides to stimulate, inhibit or regulate many body functions. The development of radiolabelled peptide-based radiopharmaceuticals for imaging a variety of tumours, infection/inflammation and thrombus has seen a new era in nuclear medicine. Recently, a number of 99Tcm-labelled bioactive peptides have proven to be useful diagnostic imaging agents. Due to their small size, peptide molecules exhibit favourable pharmacokinetic characteristics, such as rapid uptake by target tissue and rapid blood clearance, which potentially allows images to be acquired earlier following the administration of a 99Tcm-labelled peptide radiopharmaceutical. The challenge is to label bioactive peptides with 99Tcm with high specific activity without impairing the biological properties of the peptides. Molecular engineering techniques now permit synthesis of a wide range of biologically active peptides that carry chelating groups in their structure without affecting their receptor binding properties, thus permitting a high specific activity product. This review presents recent developments in 99Tcm-labelled small peptides and their potential applications in the imaging of various types of diseases. In addition, the different techniques for radiolabelling small bioactive peptides, the pharmacokinetic properties of peptides, and their potential as diagnostic imaging agents are also addressed.     

Non-oncologic applications of radiolabeled peptides in nuclear medicine.

Radiolabeled peptides have been investigated for diagnostic imaging in a variety of non-oncologic diseases. For imaging thromboembolic disease, peptides which bind to various components of thrombi have been tested. For targeting the fibrin component of thrombi, peptide analogues of fibrin or fragments of fibronectin which have a distinct binding domain for fibrin have been studied. For targeting activated platelets within thrombi, linear and cyclic peptide antagonists of the glycoprotein IIb/IIIa receptor on platelets have been studied, as well as naturally occurring antagonists of this receptor which are found in venoms. Analogues of laminin and thrombospondin which bind to other receptors on platelets have also been tested. There is an approach which uses a peptide to target thrombin which is sequestered within a fibrin clot. Another area of investigation has been to develop an improved radiopharmaceutical for imaging sites of infection and/or inflammation. Peptides which would bind to leukocytes in vivo, such as antagonists to the tuftsin receptor, chemotactic peptides, interleukin-8, or a platelet factor 4 analogue, have been radiolabeled for this purpose. These agents would enable imaging of both infection and inflammation. Development of a radiopharmaceutical for specifically imaging infection has focused on antimicrobial peptides such as human neutrophil defensin, ubiquicidin, human lactoferrin and alafosfalin, which are expected to bind selectively to microorganisms and not to leukocytes. Radiolabeled peptides are also being explored as agents for assessing unstable atherosclerotic plaque (endothelin), amyloid deposits (amyloid beta peptides), and the consequences of diabetes mellitus (human C-peptide).     

Radio-labeled receptor-binding peptides: a new class of radiopharmaceuticals

Radio-labeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals. In vertebrates, these peptides transmit their biological function by binding to their specific receptor on the target cell surface. This specific receptor-binding property is exploited when the radio-labeled peptide is used as a radiopharmaceutical. The high-binding affinity for its receptor facilitates retention of the peptide in receptor-expressing tissues, whereas its relatively small size facilitates rapid clearance from the blood and other nontarget tissues. Receptor-binding peptides labeled with gamma-emitters can be used to visualize receptor-positive cells in vivo. In addition, when labeled with beta- or alpha-emitters, these peptides can be used for peptide-receptor radionuclide therapy. Various receptors are overexpressed on particular tumor types, and peptides binding to these receptors can be used to visualize tumor lesions scintigraphically. Furthermore, peptides binding receptors on granulocytes can be used to image infectious and inflammatory foci, whereas peptides binding receptors on activated thrombocytes can be used for thrombus imaging. Here, the peptide analogs that are under development for these applications are reviewed.     

Altering pharmacokinetics of radiolabeled antibodies by the interposition of metabolizable linkages. Metabolizable linkers and pharmacokinetics of monoclonal antibodies.

Monoclonal antibodies, their fragments and low molecular weight oncophilic molecules such as synthetic somatostatin derivatives have been used to deliver radioactivity to target cells for both diagnostic and therapeutic purposes. Clinical studies demonstrated high abilities of the radiolabeled antibodies and peptides for nuclear medicine applications. However, high and persistent localization of radioactivity was observed in the liver or kidney especially when these molecules are labeled with metallic radionuclides, which reduce diagnostic accuracy and compromise therapeutic effectiveness. Thus, radiolabeled antibodies and peptides would become much more useful in both targeted imaging and radiotherapy if the undesirable radioactivity localization can be diminished. As a means to reduce the undesirable radioactivity, interposition of a metabolizable linkage between an antibody and a radiolabel was proposed to generate radiolabeled small molecules of urinary excretion from the parental antibody by enzymatic cleavage of the linkage. In this paper, after indicating the rationale behind the radiopharmaceutical design, a significant role played by the interposition of the metabolizable linkage in altering pharmacokinetics of radiolabeled antibodies is described from a variety of studies so far reported with an emphasis being laid on the importance of radiometabolite-based design of metabolizable linkages.     

Radiolabelled peptides and low molecular weight proteins in metabolic diseases.

During the last decade there has been a tremendous effort to develop labelled peptides for diagnosis and therapy. The main goal has been to develop tumor imaging/therapeutic agents, as well as peptides directed to the study of thrombosis and infection. Relatively few efforts have been made to develop peptides directed to the study of metabolic diseases. Ideally, a peptide suitable for the study of metabolism should be constructed keeping in mind the following characteristics: a) preserved affinity constant, b) preserved or improved specificity for its binding site, c) increased biological half-life in comparison with the parent peptide, d) labelling with a g or positron emitter whose physical half-life fits with the biological half-life, e) strong binding of the nuclide to the molecule so that it cannot be released after internalization. In this paper some of the peptides or low molecular weight proteins along with some analogues which have been employed in experimental studies and in humans are reviewed, with major emphasis on amyloid seekers, insulin and leptin. Many of these radiopharmaceuticals have been labelled with iodine isotopes, however their in vivo application suffer of severe limitations due to rapid release of iodine after internalization. On the other hand, new perspectives are opened by new radiofluorination techniques, which offer the unique advantage to quantify organ uptake and kinetics, parameters which are of paramount importance in metabolic studies.     

In vivo neurochemistry with emission tomography and magnetic resonance spectroscopy: clinical applications

The assessment of neurochemical processes in vivo has received much attention in the past decade as techniques such as positron or single photon emission tomography (PET and SPET), and magnetic resonance spectroscopy (MRS) have become more available. With PET and SPET, basic processes, such as blood flow and oxygen or glucose metabolism, can be regionally assessed, along with more specific functions such as the production, release, and reuptake of neurotransmitters and their occupancy of specific receptors. At the same time, MRS can reveal changes in concentration of several hydrogenate compounds in the brain. All these methods have been extensively applied for research in neurology, and some applications have reached the clinical level, namely for the study of degenerative diseases, motor-neuron diseases, movement disorders, cerebrovascular diseases, and epilepsy. This article focuses on the most relevant information that can be obtained with these complementary techniques to help clinicians in the assessment of neurological diseases.     

Radiolabeled peptides in diagnosis and therapy

During the past few years, there has been exponential growth in the development of radiolabeled peptides for diagnosis and therapy. This is because the peptides can be synthesized easily and inexpensively, they have fast clearance and rapid tissue penetration, and they are less likely to be immunogenic. More importantly, most peptides have a high affinity for characteristic receptor molecules that are overexpressed on malignant mammalian cells. Peptides can be labeled with a variety of radionuclides intended for specific applications, diagnostic or therapeutic, by using both conventional and novel chelating moieties, many of which can be incorporated during the solid state synthesis of a chosen peptide. High specific-activity peptides can be prepared and used to minimize unwanted physiologic effects, and known sequences of amino acids can be modified to slow their in vivo catabolic rate. These characteristics have paved the way for the preparation of a large number of radiolabeled peptides for a variety of clinical and experimental applications. This article briefly discusses the peptide chemistry; it also summarizes the preparation of radiolabeled peptides and outlines their applications in imaging vascular thrombosis, detecting infection and inflammation, and localizing tumors. Their therapeutic applications in oncology are also presented and the future directions outlined. Peptides that have been approved for human use, such as AcuTect (Diatide, Londonderry, NH) or OctreoScan (Mallinckrodt, St. Louis, MO), or those that have made it to clinical trials, are emphasized. Also discussed are selected promising agents that are still in preclinical investigation.     

The case for ultrasound of muscles and tendons

Ultrasound is a highly sensitive technique that can be conveniently employed in the evaluation of muscle lesions of many types, ranging from neuromuscular diseases seen by neurologists to mass lesions and injuries seen by orthopedists. The technique is perhaps underutilized given its utility in these applications compared with other cross-sectional imaging techniques. Particularly when recent developments, such as extended field of view and color Doppler techniques, are integrated, ultrasound becomes highly attractive in the imaging evaluation of various lesions. This article reviews characteristic ultrasound appearances of various muscle and tendon lesions and discusses various newer techniques and interventional applications.     

Measurements of nuclear data parameters of 201Tl by gamma-ray spectrometry.

201Tl is frequently used in radiopharmaceutical applications, and therefore the gamma-ray emission probabilities and half-life have been re-determined by means of gamma-ray spectroscopy. While the activity was calibrated using the sum-peak coincidence method, the half-life was obtained by the reference source method based on simultaneous counting of a reference source and the sample. Both the measurement techniques and assignment of uncertainties are presented and discussed, and the resulting data are shown to be in good agreement with previously published studies.     

Peptide receptor imaging and therapy.

This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendocrine tumors, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, gastrinomas, and paragangliomas, or other diseases in which somatostatin receptors may also be expressed, like sarcoidosis and autoimmune diseases. [(111)In-DTPA0]octreotide is a radiopharmaceutical that has great potential for helping visualize whether somatostatin receptor-positive tumors have recurred. The overall sensitivity of SRI to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of SRI in the localization or staging procedure may be very rewarding in terms of cost effectiveness, patient management, or quality of life. The value of SRI in patients with other tumors, such as breast cancer or malignant lymphomas, or in patients with granulomatous diseases has to be established. The application of radiolabeled peptides may be clinically useful in another way: after the injection of [(111)In-DTPA0]octreotide, surgeons can detect tumor localizations by a probe that is used during the operation. This may be of particular value if small tumors with a high receptor density are present (e.g., gastrinomas). As the success of peptide receptor scintigraphy for tumor visualization became clear, the next logical step was to try to label these peptides with radionuclides emitting alpha or beta particles, or Auger or conversion electrons, and to perform radiotherapy with these radiolabeled peptides. The results of the described studies with 90Y- and (111)In-labeled octreotide show that peptide receptor radionuclide therapy using radionuclides with appropriate particle ranges may become a new treatment modality. One might consider the use of radiolabeled somatostatin analogs first in an adjuvant setting after surgery of somatostatin receptor-positive tumors to eradicate occult metastases and second for cancer treatment at a later stage.     

Fourier-transform infrared spectroscopy: A universal optical sensing technique with auspicious application prospects in the diagnosis and management of autoimmune diseases

Autoimmune diseases (AIDs) are poorly understood clinical syndromes due to breakdown of immune tolerance towards specific types of self-antigens. They are generally associated with an inflammatory response mediated by lymphocytes, autoantibodies or both. Ultimately, chronic inflammation culminates in tissue damages and clinical manifestations. AIDs affect 5% of the world population, and they represent the main cause of fatality in young to middle-aged females. In addition, the chronic nature of AIDs has a devastating impact on the patient's quality of life. It also places a heavy burden on the health care system. Establishing a rapid and accurate diagnosis is considered vital for an ideal medical management of these autoimmune disorders. However, for some AIDs, this task might be challenging. Vibrational spectroscopies, and more particularly Fourier-transform infrared (FTIR) spectroscopy, have emerged as universal analytical techniques with promising applications in the diagnosis of various types of malignancies and metabolic and infectious diseases. The high sensitivity of these optical sensing techniques and their minimal requirements for test reagents qualify them to be ideal analytical techniques. The aim of the current review is to explore the potential applications of FTIR spectroscopy in the diagnosis and management of most common AIDs. It also aims to demonstrate how this technique has contributed to deciphering the biochemical and physiopathological aspects of these chronic inflammatory diseases. The advantages that can be offered by this optical sensing technique over the traditional and gold standard methods used in the diagnosis of these autoimmune disorders have also been extensively discussed.     

Molecular Imaging of Biological Gene Delivery Vehicles for Targeted Cancer Therapy: Beyond Viral Vectors

Cancer persists as one of the most devastating diseases in the world. Problems including metastasis and tumor resistance to chemotherapy and radiotherapy have seriously limited the therapeutic effects of present clinical treatments. To overcome these limitations, cancer gene therapy has been developed over the last two decades for a broad spectrum of applications, from gene replacement and knockdown to vaccination, each with different requirements for gene delivery. So far, a number of genes and delivery vectors have been investigated, and significant progress has been made with several gene therapy modalities in clinical trials. Viral vectors and synthetic liposomes have emerged as the vehicles of choice for many applications. However, both have limitations and risks that restrict gene therapy applications, including the complexity of production, limited packaging capacity, and unfavorable immunological features. While continuing to improve these vectors, it is important to investigate other options, particularly nonviral biological agents such as bacteria, bacteriophages, and bacteria-like particles. Recently, many molecular imaging techniques for safe, repeated, and high-resolution in vivo imaging of gene expression have been employed to assess vector-mediated gene expression in living subjects. In this review, molecular imaging techniques for monitoring biological gene delivery vehicles are described, and the specific use of these methods at different steps is illustrated. Linking molecular imaging to gene therapy will eventually help to develop novel gene delivery vehicles for preclinical study and support the development of future human applications.     

用于PET放射性药物合成的微流体芯片

微流体芯片在有机合成领域显示了它独特的优势,而应用到放射性药物合成领域却很少.最近,国际上几个科研小组证实了微流体芯片在放射性药物合成上的潜力,并证实传统放射合成的许多步骤均可被微流体芯片所取代.同时也证实以微流体芯片为基础的放射性化学合成比传统的放射性化学合成使用的前体量更少,反应速度更快,合成出的药品有更高的比活度和产率,纯化过程也更简单,同时对放射性的防护也更容易.尽管有如此多的优点,但目前还没有被广泛的商业开发.本文对目前国际上主要的几种微流体芯片的优缺点及其在PET药物合成中的应用进行了综述.     

Computed tomography in nuclear medicine

Utilizing mathematical techniques and computer processing similar to those employed in x-ray transmission computed tomography and magnetic resonance imaging, cross-sectional images of radiopharmaceutical distribution are demonstrating encouraging maps of organ physiology and pathophysiology. The basic concepts of single photon emission computed tomography (SPECT), and some of its clinical implications, are presented to demonstrate the potential applications of this new modality.     

Radiolabeled chemotactic cytokines: new agents for scintigraphic imaging of infection and inflammation.

Several radiopharmaceuticals are currently used for diagnosis of inflammatory and infectious diseases in patients. Most inflammatory and infectious processes can be visualized with radiolabeled autologous leukocytes, currently considered to be the most appropriate radiopharmaceutical for this purpose. This agent is very well capable to delineate most inflammatory and infectious foci in a relatively short time after injection. The time-consuming and intricate labeling procedure and the handling of potentially contaminated blood, however cause that there is a great interest in the development of new radiopharmaceuticals comprising the same imaging qualities but without these disadvantages. Besides radiolabeled leukocytes several other radiopharmaceuticals, such as (67)Ga-citrate, radiolabeled anti-granulocyte antibodies and FDG are used to image infection and inflammation. These agents accumulate in infectious and inflammatory lesions in a non-specific manner or have suboptimal diagnostic characteristics. Nowadays, there is a great interest in the development of radiolabeled chemotactic and chemokinetic cytokines that accumulate and are retained in infectious and inflammatory foci by specific interaction with infiltrated inflammatory cells. In this review we describe the specific characteristics of the chemotactic and chemokinetic compounds that are currently studied as potential radiopharmaceutical to visualize infectious and inflammatory foci. The characteristics of a series of cytokines (IL-1, IL-2), chemokines (IL-8, PF-4, MCP-1, NAP-2), complement factors (C5a, C5adR), chemotactic peptides (fMLF) and other chemotactic factors (LTB4) are described. The potentials of these compounds to serve as an imaging agent are discussed.     

Update on PET radiopharmaceuticals: life beyond fluorodeoxyglucose

Twenty-eight years after its inception, 2-[18F]FDG- is still the most widely used radiopharmaceutical for PET studies, but numerous more specific radiotracers have been developed and applied in neuroscience and oncology. The advances in radiotracer chemistry, especially the nucleophilic substitution reaction, have played the pivotal role in synthesizing various no-carrier-added 18F-labeled radiotracers for PET studies of various receptor systems. This article lists some of the radiotracers that are available for PET studies in neuroscience and oncology. The prospects for developing other new radiotracers for imaging other organ diseases also seem to be promising.     

Ultrasound in sports medicine: relevance of emerging techniques to clinical care of athletes

The applications of ultrasound in managing the clinical care of athletes have been expanding over the past decade. This review provides an analysis of the research that has been published regarding the use of ultrasound in athletes and focuses on how these emerging techniques can impact the clinical management of athletes by sports medicine physicians. Electronic database literature searches were performed using the subject terms 'ultrasound' and 'athletes' from the years 2003 to 2012. The following databases were searched: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus?. The search produced 617 articles in total, with a predominance of articles focused on cardiac and musculoskeletal ultrasound. 266 of the studies involved application of ultrasound in evaluating the cardiovascular properties of athletes, and 151 studies involved musculoskeletal ultrasound. Other applications of ultrasound included abdominal, vascular, bone density and volume status. New techniques in echocardiography have made significant contributions to the understanding of the physiological changes that occur in the athlete's heart in response to the haemodynamic stress associated with different types of activity. The likely application of these techniques will be in managing athletes with hypertrophic cardiomyopathy, and the techniques are near ready for application into clinical practice. These techniques are highly specialized, however, and will require referral to dedicated laboratories to influence the clinical management of athletes. Investigation of aortic root pathology and pulmonary vascular haemodynamics are also emerging, but will require additional studies with larger numbers and outcomes analysis to validate their clinical utility. Some of these techniques are relatively simple, and thus hold the potential to enter clinical management in a point-of-care fashion. Musculoskeletal ultrasound has demonstrated a number of diagnostic and therapeutic techniques applicable to pathology of the shoulder, elbow, wrist, hand, hip, knee and ankle. These techniques have been applied mainly to the management of impingement syndromes, tendinopathies and arthritis. Many of these techniques have been validated and have entered clinical practice, while more recently developed techniques (such as dynamic ultrasound and platelet-rich plasma injections) will require further research to verify efficacy. Research in musculoskeletal ultrasound has also been helpful in identifying risk factors for injury and, thus, serving as a focus for developing interventions. Research in abdominal ultrasound has investigated the potential role of ultrasound imaging in assessing splenomegaly in athletes with mononucleosis, in an attempt to inform decisions and policies regarding return to play. Future research will have to demonstrate a reduction in adverse events in order to justify the application of such a technique into policy. The role of ultrasound in assessing groin pain and abdominal pain in ultraendurance athletes has also been investigated, providing promising areas of focus for the development of treatment interventions and physical therapy. Finally, preliminary research has also identified the role of ultrasound in addressing vascular disease, bone density and volume status in athletes. The potential applications of ultrasound in athletes are broad, and continuing research, including larger outcome studies, will be required to establish the clinical utility of these techniques in the care of athletes.     

Technetium 99m sestamibi in the assessment of acute myocardial infarction.

Technetium 99m sestamibi is a promising new radiopharmaceutical that can assess myocardium at risk, infarct size, and treatment efficacy in acute myocardial infarction. The minimal redistribution of this radiopharmaceutical makes it ideal for the measurement of myocardium at risk, as demonstrated by several animal studies. The high-count density images are readily quantitated, and techniques have been developed and validated for this purpose. Early clinical studies have shown that myocardium at risk varies widely, even for a coronary occlusion in a similar location, a finding similar to that reported previously in several different animal infarction models. The clinical use of this radiopharmaceutical to measure final infarct size and treatment benefit, or myocardial salvage, has now been demonstrated using both planar and tomographic imaging techniques. Evidence of benefit is often evident by 18 to 48 hours after reperfusion therapy, although the full extent of improvement is not evident until later. The current 6-hour shelf life and 30-minute preparation time are logistical barriers to widespread clinical use. This radiopharmaceutical provides a new, powerful measurement tool for the assessment of treatment efficacy in acute myocardial infarction that is probably superior to other currently available methods.     

Potential of MR-imaging in the paediatric abdomen

OBJECTIVE: To describe the potential and relevant applications of MR-imaging (MRI) in typical paediatric abdominal conditions and diseases. METHOD: The commonly used indications, applications, and sequences as well as typical imaging findings of paediatric abdominal MRI are presented and discussed, with emphasis on specific paediatric needs and queries. Only applications as used in routine clinical work are listed, other more sophisticated and advanced techniques will only briefly be mentioned. Furthermore, some aspects of paediatric MR Urography are presented and discussed. CONCLUSION: Though conventional imaging methods (ultrasound and plain film) are valuable and - particularly in the paediatric abdomen - form the mainstay of routine imaging in paediatric abdominal radiology, some conditions require sectional imaging. MRI is increasingly applied to these queries in neonates, infants and children as an alternative method to CT without any radiation burden, and - when performed adequately and skilfully - can answer most treatment relevant questions. MR will increasingly be applied with new applications and broader availability also with functional information deriving from new equipment and research offering an ideal one stop imaging approach to many conditions also in children.