Targeting peptides and positron emission tomography

Biologically active peptides have during the last decades made their way into conventional nuclear medicine diagnosis using single photon emission computed tomography (SPECT) and gamma-camera. Several clinical trails are also investigating the role of radiolabeled peptides for targeting radionuclide therapy. This has raised the question as to whether positron emission tomography (PET) can be used in order to obtain better quantitative information of the peptide distribution in tumor and healthy organs, i.e., to get a better dosimetry. Positron emitting analogs of the therapeutic radionuclides used have been produced and successfully applied in peptide pharmacokinetic measurements with PET. But the recent boom in (18)FDG-PET ((18)FDG = [(18)F]2-deoxy-2-fluoro-D-glucose), and with this a worldwide increasing number of PET systems, has also inspired several research groups to hunt for alternative labels to be used for peptide diagnostics and PET. The rapid kinetic of short peptides agrees well with the short half-lives of standard PET nuclides like (11)C and (18)F. Especially, (18)F appears to be excellent for labeling bioactive peptides due to its favorable physical and nuclear characteristics. However, with present techniques labeling peptides with (18)F is laborious and time-consuming, and is not yet a clinical alternative. Other halogens like (75, 76)Br and (124)I are, from the chemical point of view, easier to apply. But an even better labeling alternative may be positron emitting metal ions like (55)Co, (68)Ga, and (110m)In since they tend to give better intracellular retention and thus a better signal-to-background ratio than the halogen labels. The main drawback with these radionuclides is that they are not readily available. Some of these radionuclides also emit gamma in their decay that may affect the measuring properties of the PET equipment. This article reviews mainly the present situation of production and use of nonconventional positron emitters for peptide labeling.     

Regional changes in extravascular lung water detected by positron emission tomography

Regional measurements of extravascular lung water (rEVLW) were made with positron emission tomography (PET) and 15O-labeled radionuclides. The label used to measure the total lung water (TLW) content fully equilibrated with TLW prior to scanning in both dogs with normal and low cardiac outputs, and nearly so in areas of lung made edematous by oleic acid injury (the TLW values used were 97% of maximum values). Regional EVLW measurements made by PET (EVLW-PET) and gravimetric techniques in both normal and edematous lung were closely correlated (r = 0.93), and EVLW-PET increased from an average of 0.20 to 0.37 mlH2O/ml lung (P less than 0.05) after regional lung injury. PET measurements of regional blood volume always decreased [from an average of 0.12 to 0.09 ml blood/ml lung (P less than 0.05)] after cardiac output was lowered by hemorrhage in a separate set of animals. Total EVLW (by thermodye indicator dilution) did not change. Likewise, regional EVLW remained constant in areas below the left atrium but decreased in areas above the left atrium. We conclude that PET measurements are accurate, noninvasive, and reproducible and that regional changes may be detected even when measurements of total EVLW by other methods may fail to change significantly.     

Évaluation de la perfusion myocardique par TEP-TDM

For the past decade, PET and PET/CT have been widely studied for myocardial perfusion imaging. Several studies demonstrated the incremental value of PET for the diagnostic and prognostic assessment of patients with coronary artery disease. Moreover, PET allows for non-invasively quantifying myocardial blood flow and myocardial flow reserve, that both are recognized as surrogate marker of cardiac event free survival. By enabling the exploration of epicardial disease and the microvasculature, PET constitutes a unique tool to study pathophysiogical mechanisms leading to atherosclerosis genesis. The recent emergence of high-tech hybrid machines may even provide further incremental information about coronary function and morphology. By taking the best of each modality, a better assessment of patients with coronary artery disease is expected.     

PET as a potential tool for imaging molecular mechanisms of oncology in man

During the past ten years, positron emission tomography (PET) has been increasingly developed for imaging and quantifying molecular mechanisms in oncology. The technique uses radionuclides to label molecules, which can then be imaged in man. The inherent sensitivity and specificity of PET is unrivalled because it can image molecular interactions and pathways, providing quantitative kinetic information down to the subpicomolar level. This technology has the potential to answer a large number of important clinical questions in translational research in oncology. However, the challenges in the methodology are substantial. Molecular imaging has the potential to assist in the optimization of molecular-based targeted therapies in cancer and to investigate the function of the genome.     

Antibody fragments labeled with fluorine-18 and gallium-68: In vivo comparison with indium-111 and iodine-125-labeled fragments

Although monoclonal antibodies have been radiolabeled with many different radionuclides, the application of positron emission tomography (PET) to the imaging of radiolabeled antibodies has been limited to the investigation of a small number of long-lived radionuclides. In this study, we labeled F(ab′)₂ fragments of a mouse monoclonal antibody (BB5-G1) specific for a human parathyroid surface antigen with the positron emitting radionuclides, gallium-68 and fluorine-18. The biodistribution of the fragments was evaluated in a nude mice model and the results were compared to those obtained with fragments labeled with iodine-125 and indium-111 using conventional labeling techniques. All labeled fragments bound to human parathyroid tissue implanted in nude mice, with parathyroid-to-muscle ratios reaching as high as 10:1, 4 h after administration. A major difference was observed in the uptake and clearance of the various labeled fragments through the kidney. The halogen activity cleared, but the metal radioactivity was retained in the kidney. The results indicate that the fluorine-18 or gallium-68 labeled fragment may be useful for parathyroid imaging with positron emission tomography.     

Model-checking techniques based on cumulative residuals

Residuals have long been used for graphical and numerical examinations of the adequacy of regression models. Conventional residual analysis based on the plots of raw residuals or their smoothed curves is highly subjective, whereas most numerical goodness-of-fit tests provide little information about the nature of model misspecification. In this paper, we develop objective and informative model-checking techniques by taking the cumulative sums of residuals over certain coordinates (e.g., covariates or fitted values) or by considering some related aggregates of residuals, such as moving sums and moving averages. For a variety of statistical models and data structures, including generalized linear models with independent or dependent observations, the distributions of these stochastic processes tinder the assumed model can be approximated by the distributions of certain zero-mean Gaussian processes whose realizations can be easily generated by computer simulation. Each observed process can then be compared, both graphically and numerically, with a number of realizations from the Gaussian process. Such comparisons enable one to assess objectively whether a trend seen in a residual plot reflects model misspecification or natural variation. The proposed techniques are particularly useful in checking the functional form of a covariate and the link function. Illustrations with several medical studies are provided.     

Brain imaging in nonhuman primates: insights into drug addiction

In vivo brain imaging enables the systematic examination of trait and state variables that contribute to the etiology of human diseases. This review highlights the use of in vivo imaging in nonhuman primate models of drug abuse. In efforts to translate findings from laboratory animals to humans, monkey models offer considerable advantages over those that use rodents and other species because of their neurobiological similarity to humans and their longer life span, which makes it possible to study individual subjects over several years. This article provides a brief overview of positron emission tomography (PET), magnetic resonance imaging (MRI)-based techniques, and encephalographic approaches, with a focus on methodological issues that investigators new to the field should consider. We discuss PET imaging studies involving the dopamine (DA) system, with a special emphasis on DA D2 receptors, and describe experimental approaches through which PET imaging data can provide information about the neuropharmacological and neurochemical actions of drugs that modify behavior. We also consider the use of imaging to understand the impact and interactions of genetic predispositions and environmental and physiological modulators on disease states. For MRI-based and encephalographic studies, we describe approaches that can provide new information about brain function. Although much work remains to be done to adapt and apply these techniques for routine use in nonhuman primates, there has been much progress. These techniques will provide the foundation for future studies aimed at developing behavioral and pharmacological treatments for many human diseases.     

Imaging neurodegeneration in Parkinson's disease

Neuroimaging techniques have evolved over the past several years giving us unprecedented information about the degenerative process in Parkinson's disease (PD) and other movement disorders. Functional imaging approaches such as positron emission tomography (PET) and single photon emission computerised tomography (SPECT) have been successfully employed to detect dopaminergic dysfunction in PD, even while at a preclinical stage, and to demonstrate the effects of therapies on function of intact dopaminergic neurons within the affected striatum. PET and SPECT can also monitor PD progression as reflected by changes in brain levodopa and glucose metabolism and dopamine transporter binding. Structural imaging approaches include magnetic resonance imaging (MRI) and transcranial sonography (TCS). Recent advances in voxel-based morphometry and diffusion-weighted MRI have provided exciting potential applications for the differential diagnosis of parkinsonian syndromes. Substantia nigra hyperechogenicity, detected with TCS, may provide a marker of susceptibility to PD, probably reflecting disturbances of iron metabolism, but does not appear to correlate well with disease severity or change with disease progression. In the future novel radiotracers may help us assess the involvement of non-dopaminergic brain pathways in the pathology of both motor and non-motor complications in PD.     

聚对苯二甲酸乙二醇酯水解酶检测方法的研究进展

聚对苯二甲酸乙二醇酯(polyethylene terephthalate,PET)是应用最广泛的合成聚酯之一。由于PET不易降解,在环境中积累,对陆地、水生生态系统以及人类健康构成严重威胁。基于生物酶催化的生物降解策略为PET回收利用提供了一种绿色途径,在过去20年间,已发现了多种PET水解酶,并通过蛋白质工程等手段来改善这些酶的降解性能,但是目前仍未找到适合大规模工业应用的PET水解酶。利用传统的检测方法筛选PET水解酶是一个缓慢而复杂的过程。为了促进PET酶法回收的工业化应用,需要研发高效的检测方法。近年来,研究人员开发了多种表征PET水解酶的分析方法。本文总结了可用于筛选PET水解酶的检测方法,如高效液相色谱法、紫外吸光度法和荧光激活液滴分选法等,并对其在筛选PET水解酶的应用方面进行了展望。     

A fly's eye view of biology.

Determining how genes function in developmentally complex multicellular organisms can be a formidable task. Obstacles arise from the fact that inactivation of most genes results in subtle or undetectable phenotypic alterations, and when phenotypes are observed they are often difficult to interpret because most genes play multiple roles in development. New techniques that have been applied to studying genes in the developing Drosophila eye promise to circumvent these obstacles. The advent of these techniques combined with the existing wealth of information about cellular pattern formation in the Drosophila eye make the eye a powerful model system for deciphering the function of genes in biological processes.     

A geographical information system model for creating bioclimatic maps – examples from a high,mid-latitude city

This paper presents a method for creating large-scale bioclimatic maps with the aid of a geographical information system, GIS. Meteorological data are linked with geographical information about land use, elevation and distance to the coast, in order to generate spatial distributions of physiological equivalent temperature, PET. The model combines an air temperature map and a wind map in order to create different zones for which the thermal component is to be calculated. The advantage of the model presented is that it uses generally available information about land use, altitude and distance to the coast. Further, the model uses a GIS application, which makes it non-static. Compared to most other models, a wide range of observations are used as input. Few biometeorological studies have been performed in high-latitude areas. This paper presents bioclimatic maps for the G?teborg urban area, in Sweden, for the month of July. The results show large variations in PET during a clear, calm day at 1200 hours (Delta T 13.4 degrees C) and during average conditions in July (Delta T 6.8 degrees C), which gives an indication of the magnitude and the spatial variations within high, midlatitude, urban area in summer. The highest PET values were found in the central built-up areas and the lowest PET values in the coastal and green areas. The model generates valuable information for urban planners and decision makers when planning and constructing new areas for outdoor activities etc. This information is also useful in the fields of health and energy.     

Measuring drug-related receptor occupancy with positron emission tomography

Several techniques can be used to measure indirectly the effect of drugs (e.g., EEG, fMRI) in healthy volunteers and in patients. Although each technique has its merits, a direct link between drug efficacy and site of action in vivo usually cannot be established. In addition, when the specific mode of action of a drug has been determined from preclinical studies, it is often not known whether the administered dose is optimal for humans. Both industry and academia are becoming more and more interested in determining the dose-related occupancy of specific targets caused by administration of drugs under test. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are noninvasive imaging techniques that can give insight into the relationship between target occupancy and drug efficacy, provided a suitable radioligand is available. Although SPECT has certain advantages (e.g., a long half-life of the radionuclides), the spatial and temporal resolution as well as the labeling possibilities of this technique are limited. This review focuses on PET methodology for conducting drug occupancy studies in humans.     

TEP/TDM au FDG et toxicité pulmonaire à la bléomycine : à propos d’un cas clinique

Patients treated with bleomycin should be frequently monitored during and after treatment. Actually this treatment can cause pulmonary toxicity and may progress to pulmonary fibrosis. Extreme care is required in patients with a severe deterioration of renal function or impaired lung function. PET/CT can be a useful tool for the early diagnosis of this complication. We report a case of bleomycin-induced pneumonitis and discovered during a PET/CT performed for evaluation of Hodgkin's disease.     

Role and Cost Effectiveness of PET/CT in Management of Patients with Cancer

PET/CT is a relatively new imaging technology, whose undoubted advantages are valuable in clinical oncology as well as in all fields of diagnosis, staging, and treatment. The hardware combination of anatomy and function has been the true evolution in imaging. PET using 18F-fluorodeoxyglucose (FDG) is increasingly used for the staging of solid malignancies, including colon, lung, etc., but anatomic information is limited. Integrated PET/CT enables optimal anatomic delineation of PET findings and identification of FDG-negative lesions on computed tomography (CT) images and might improve preoperative staging. However, controversy still exists in relation to the application of PET/CT in clinical practice, mainly because of its high cost. It is evident that apart from additional costs, potential savings also are associated with PET/CT as a result of avoiding additional imaging examinations or invasive procedures and by helping clinicians make the optimum treatment decisions. The authors review the literature on the role of PET/CT in management of various tumors and discuss the medicoeconomic usefulness.     

PET imaging of the basal ganglia

The present chapter reviews PET imaging in basal ganglia disorders; Parkinson's disease is used as a model of these disorders because the neurochemical pathobiology of this disease is well known and great advances in the imaging area have been achieved. Other basal ganglia disorders including Tourette's syndrome, dystonia, Huntington's chorea and Wilson's disease are also dealt with. With PET and SPECT techniques, the whole integrative dopaminergic network of neurons can be studied, which plays an important role in differential diagnostics. Furthermore, pharmacological effects of medication can be visualized and the role of stereotaxic neurosurgery can be evaluated. Finally, functional imaging gives clues about the prognosis and rehabilitation aspects of the basal ganglia disorders.     

Cerenkov Luminescence Imaging (CLI) for Cancer Therapy Monitoring

In molecular imaging, positron emission tomography (PET) and optical imaging (OI) are two of the most important and thus most widely used modalities^1-3. PET is characterized by its excellent sensitivity and quantification ability while OI is notable for non-radiation, relative low cost, short scanning time, high throughput, and wide availability to basic researchers. However, both modalities have their shortcomings as well. PET suffers from poor spatial resolution and high cost, while OI is mostly limited to preclinical applications because of its limited tissue penetration along with prominent scattering optical signals through the thickness of living tissues.Recently a bridge between PET and OI has emerged with the discovery of Cerenkov Luminescence Imaging (CLI)^4-6. CLI is a new imaging modality that harnesses Cerenkov Radiation (CR) to image radionuclides with OI instruments. Russian Nobel laureate Alekseyevich Cerenkov and his colleagues originally discovered CR in 1934. It is a form of electromagnetic radiation emitted when a charged particle travels at a superluminal speed in a dielectric medium^7,8. The charged particle, whether positron or electron, perturbs the electromagnetic field of the medium by displacing the electrons in its atoms. After passing of the disruption photons are emitted as the displaced electrons return to the ground state. For instance, one ¹⁸F decay was estimated to produce an average of 3 photons in water⁵. Since its emergence, CLI has been investigated for its use in a variety of preclinical applications including in vivo tumor imaging, reporter gene imaging, radiotracer development, multimodality imaging, among others^4,5,9,10,11. The most important reason why CLI has enjoyed much success so far is that this new technology takes advantage of the low cost and wide availability of OI to image radionuclides, which used to be imaged only by more expensive and less available nuclear imaging modalities such as PET.Here, we present the method of using CLI to monitor cancer drug therapy. Our group has recently investigated this new application and validated its feasibility by a proof-of-concept study¹². We demonstrated that CLI and PET exhibited excellent correlations across different tumor xenografts and imaging probes. This is consistent with the overarching principle of CR that CLI essentially visualizes the same radionuclides as PET. We selected Bevacizumab (Avastin; Genentech/Roche) as our therapeutic agent because it is a well-known angiogenesis inhibitor^13,14. Maturation of this technology in the near future can be envisioned to have a significant impact on preclinical drug development, screening, as well as therapy monitoring of patients receiving treatments.     

Small animal PET imaging

Positron emission tomography (PET) is well established as an important research and clinical molecular imaging modality. Although the size differences between humans and rodents create formidable challenges for the application of PET imaging in small animals, advances in technology over the past several years have enabled the translation of this imaging modality to preclinical applications. In this article we discuss the basic principles of PET instrumentation and radiopharmaceuticals, and examine the key factors responsible for the qualitative and quantitative imaging capabilities of small animal PET systems. We describe the criteria that PET imaging agents must meet, and provide examples of small animal PET imaging to give the reader a broad perspective on the capabilities and limitations of this evolving technology. A crucial driver for future advances in PET imaging is the availability of molecular imaging probes labeled with positron-emitting radionuclides. The strong translational science potential of small animal and human PET holds great promise to dramatically advance our understanding of human disease. The assessment of molecular and functional processes using imaging agents as either direct or surrogate biomarkers will ultimately enable the characterization of disease expression in individual patients and thus facilitate tailored treatment plans that can be monitored for their effectiveness in each subject.     

Biotechnology techniques for the development of new tumor specific peptides

Peptides, proteins and antibodies are promising candidates as carriers for radionuclides in endoradiotherapy. This novel class of pharmaceuticals offers a great potential for the targeted therapy of cancer. The fact that some receptors are overexpressed in several tumor types and can be targeted by small peptides, proteins or antibodies conjugated to radionuclides has been used in the past for the development of peptide endoradiotherapeutic agents such as ⁹⁰Y-DOTATOC or radioimmunotherapy of lymphomas with Zevalin. These procedures have been shown to be powerful options for the treatment of cancer patients.Design of new peptide libraries and scaffolds combined with biopanning techniques like phage and ribosome display may lead to the discovery of new specific ligands for target structures overexpressed in malignant tumors. Display methods are high throughput systems which select for high affinity binders. These methods allow the screening of a vast amount of potential binding motifs which may be exposed to either cells overexpressing the target structures or in a cell-free system to the protein itself. Labelling these binders with radionuclides creates new potential tracers for application in diagnosis and endoradiotherapy. This review highlights the advantages and problems of phage and ribosome display for the identification and evaluation of new tumor specific peptides.     

Prior specification in Bayesian statistics: three cautionary tales

One of the most important differences between Bayesian and traditional techniques is that the former combines information available beforehand-captured in the prior distribution and reflecting the subjective state of belief before an experiment is carried out-and what the data teach us, as expressed in the likelihood function. Bayesian inference is based on the combination of prior and current information which is reflected in the posterior distribution. The fast growing implementation of Bayesian analysis techniques can be attributed to the development of fast computers and the availability of easy to use software. It has long been established that the specification of prior distributions should receive a lot of attention. Unfortunately, flat distributions are often (inappropriately) used in an automatic fashion in a wide range of types of models. We reiterate that the specification of the prior distribution should be done with great care and support this through three examples. Even in the absence of strong prior information, prior specification should be done at the appropriate scale of biological interest. This often requires incorporation of (weak) prior information based on common biological sense. Very weak and uninformative priors at one scale of the model may result in relatively strong priors at other levels affecting the posterior distribution. We present three different examples intu?vely illustrating this phenomenon indicating that this bias can be substantial (especially in small samples) and is widely present. We argue that complete ignorance or absence of prior information may not exist. Because the central theme of the Bayesian paradigm is to combine prior information with current data, authors should be encouraged to publish their raw data such that every scientist is able to perform an analysis incorporating his/her own (subjective) prior distributions.     

Streptococcus pneumoniae induced c-Jun-N-terminal kinase- and AP-1 -dependent IL-8 release by lung epithelial BEAS-2B cells

Background

Chronic lung diseases are a major issue in public health. A serial pulmonary assessment using imaging techniques free of ionizing radiation and which provides early information on local function impairment would therefore be a considerably important development. Magnetic resonance imaging (MRI) is a powerful tool for the static and dynamic imaging of many organs. Its application in lung imaging however, has been limited due to the low water content of the lung and the artefacts evident at air-tissue interfaces. Many attempts have been made to visualize local ventilation using the inhalation of hyperpolarized gases or gadolinium aerosol responding to MRI. None of these methods are applicable for broad clinical use as they require specific equipment.

Methods

We have shown previously that low-field MRI can be used for static imaging of the lung. Here we show that mathematical processing of data derived from serial MRI scans during the respiratory cycle produces good quality images of local ventilation without any contrast agent. A phantom study and investigations in 85 patients were performed.

Results

The phantom study proved our theoretical considerations. In 99 patient investigations good correlation (r = 0.8; p ≤ 0.001) was seen for pulmonary function tests and MR ventilation measurements. Small ventilation defects were visualized.

Conclusion

With this method, ventilation defects can be diagnosed long before any imaging or pulmonary function test will indicate disease. This surprisingly simple approach could easily be incorporated in clinical routine and may be a breakthrough for lung imaging and functional assessment.