Ernst Schering Research Foundation workshop

Publications in this journal

• Article: Microwaving in F-18 chemistry: quirks and tweaks.

  S Stone-Elander, N Elander, J O Thorell, A Fredriksson
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  ABSTRACT: Since the late 1980s, microwave dielectric heating has been used to speed up chemical transformations, also in radiolabeling tracers for positron emission tomography. In addition to shorter reaction times, higher yields, cleaner product mixtures and improved reproducibility have also been obtained for reactions involving polar components that require heating at elevated temperatures. The conditions used in microwave chemistry can differ considerably from those in conventional heating. Understanding the factors that influence the interaction of the electromagnetic field with the sample is critical for the successful implementation of microwave heating. These parameters are discussed here and exemplified with radiolabelings with fluorine-18.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: [18F]fluoropyridines: From conventional radiotracers to the labeling of macromolecules such as proteins and oligonucleotides.

  F Dollé
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  ABSTRACT: Molecular in vivo imaging with the high-resolution and sensitive positron emission tomography (PET) technique requires the preparation of a positron-emitting radiolabeled probe or radiotracer. For this purpose, fluorine-18 is becoming increasingly the radionuclide of choice due to its adequate physical and nuclear characteristics, and also because of the successful use in clinical oncology of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), which is currently the most widely used PET-radiopharmaceutical and probably the driving force behind the growing availability and interest for this positron-emitter in radiopharmaceutical chemistry. With a few exceptions, radiofluorinations involving fluorine-18 of high specific radioactivity (e.g. > 185 GBq/micromole) had, until recently, been limited to nucleophilic substitutions in homoaromatic and aliphatic series with [18F]fluoride. Considering chemical structures showing a fluoropyridinyl moiety, nucleophilic heteroaromatic substitution at the ortho-position with no-carrier-added [l8F]fluoride, as its K[18F]F-K222 complex, appears today as a highly efficient method for the radiosynthesis of radiotracers and radiopharmaceuticals. This chapter summarizes the recent applications of this methodology and highlights its potential in the design and preparation of, often drug-based, fluorine-18-labeled probes of high specific radioactivity for PET imaging, including macromolecules of biological interest such as peptides, proteins and oligonucleotides.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Production of non-standard PET radionuclides and the application of radiopharmaceuticals labeled with these nuclides.

  M J Welch, R Laforest, J S Lewis
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  ABSTRACT: The field of positron emission tomography (PET) has expanded dramatically over recent years. In spite of this expansion the large majority of clinical studies are carried out utilizing one radiopharmaceutical-2-fluoro-2-deoxyglucose. Many research groups are developing novel radiopharmaceuticals. A major emphasis is on other agents labeled with 18F. Several other positron emitting radionuclides can be prepared in high yields in small biomedical cyclotrons. Some of these have half-lives that make delivery significantly easier than the delivery of 18F compounds. These radionuclides include: 64Cu (half life 12.7 h), 76Br (half life 16.2 h), 86Y (half life 14.74 h) and 124I (half life 4.2 days). The method of production of these and other 'non-standard' PET radionuclides will be discussed and the method of labeling radiopharmaceuticals with these radionuclides described. Several of these radiopharmaceuticals have been studied in animal models as well and a limited number translated to the human situation.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: RNAi applications in target validation.

  A Kourtidis, C Eifert, D S Conklin
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  ABSTRACT: The emergence of systems biology is certain to transform the identification and validation of therapeutic targets in modern drug discovery. A relatively recent systems biology approach is functional genomics, which identifies the molecular mechanisms responsible for a specific phenotype by interrogating the activity of all of an organism's genes. Initially undertaken in model organisms such as Caenorhabditis elegans, Saccharomyces cerevisiae, and Drosophila melanogaster, functional genomics has now moved into the realm of mammalian cells both in vitro and in vivo due to the development of RNA interference. RNA interference is a conserved biological process that has evolved to specifically and efficiently silence genes. Genome-wide screens using RNA interference have proven powerful in elucidating components of functionally related pathways and have therefore become integral for the development of new and improved therapeutic targets. This article provides an overview of many of the systems biology approaches taken, using RNA interference, in order to demonstrate how it may be used today for drug discovery and tomorrow as a targeted therapy.
  Ernst Schering Research Foundation workshop 02/2007;
• Source

  Available from: nuim.ie

  Article: A plea for more theory in molecular biology.

  O Wolkenhauer, M Mesarović, P Wellstead
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  ABSTRACT: The integrationist principles of systems theory have proven hugely successful in the physical sciences and engineering. It is an underlying assumption made in the systems approach to biology that they can also be used to understand biological phenomena at the level of an entire organism or organ. Within this holistic vision, the vast majority of systems biology research projects investigate phenomena at the level of the cell, with the belief that unifying principles established at the most basic level can establish a framework within which we may understand phenomena at higher levels of organization. In this spirit, and to use a celestial analogy, if a disease--effecting an organ or entire body--is our universe of discourse, then the cell is the star we gaze at. In building an understanding of disease and the effect of drugs, systems biology makes an implicit assumption about direct causal entailment between cell function and physiology. A skeptic might argue that this is about the same as trying to predict the world economy from observations made at a local supermarket. However, assuming for the moment that the money and hope we are investing in molecular biology, genomics, and systems biology is justified, how should this amazing intellectual achievement be possible? In this chapter we argue that an essential tool to progress is a systems theory that allows biological objects and their operational characteristics to be captured in a succinct yet general form. Armed with this conceptual framework, we construct mathematical representations of standard cellular and intercellular functions which can be integrated to describe more general processes of cell complexes, and potentially entire organs.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Does the serum peptidome reveal hemostatic dysregulation?

  M T Davis, S D Patterson
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  ABSTRACT: There is a significant need for markers that are diagnostic of disease, particularly cancer. For these biomarkers to be useful they would need to be able to detect disease early in its progression with high sensitivity and specificity. Many approaches are being undertaken to attempt to find such biomarkers using the tools of systems biology, i.e., parallel measurement techniques including proteomics (parallel protein measurements). Often the premise behind such an approach was to cast a wide net and then design an assay for specific elements that were found to be diagnostic. One such approach has utilized matrix-assisted laser desorption/ionization-mass spectrometry to interrogate the low-molecular-weight component of serum (the fluid component of blood following clotting), the serum peptidome. This approach has the appealing characteristic of speed of analysis but has a number of shortcomings mostly due to signal:noise and mass resolution in some instruments, making peak analysis difficult. Of course, experimental design and statistical analysis have to be conducted with the system limitations in mind. These points have been addressed by others, but few have focused on a potentially larger issue with serum peptidome analysis - are the signals being measured informing us about the disease state directly or indirectly through measurement of another physiological process such as hemostatic dysregulation? This article will present evidence that points to careful measures of the serum peptidome revealing differences in clotting time in disease states and not direct measures of tumor proteolytic activity on blood proteins.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Systems biology: new paradigms for cell biology and drug design.

  H V Westerhoff
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  ABSTRACT: In this chapter various facets of and approaches to systems biology will be discussed. This then leads to an illustration of how systems biology may be used in drug target design. We present five new paradigms for drug target research and show how these are based in systems biology.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Evaluation of the effect on cardiac repolarization (QTc interval) of oncologic drugs.

  J Morganroth
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  ABSTRACT: The 12-lead electrocardiograph (ECG) is the standard safety measurement used in clinical trials to identify drug-induced cardiac adverse effects. Drug-induced prolongation of the QTc interval (the measure of cardiac repolarization change), when excessive and in conjunction with the right risk factors, can degenerate into a polymorphic ventricular tachycardia called torsades de pointes and has become a new focus for new drug development. The assessment of an ECG in clinical practice using machine-defined QTc duration is intrinsically unreliable. Current regulatory concepts have focused on the need for measuring ECG intervals using manual techniques using digital processing in a central ECG laboratory. The QT interval is subject to a large degree of spontaneous variability requiring attention to basic clinical trial design issues such as sample size (use as large a cohort as possible), frequency of measurements taken (at least three to six ECGs at baseline and at many time points on therapy with pharmacokinetic samples if possible), and their accuracy. Since most oncologic products are cytotoxic, a Thorough or Dedicated ECG Trial cannot be conducted and in the usual trail, especially in phase I, all changes seen on the ECG will be attributed to the new oncology drug. For most nononcologic drugs, there is regulatory guidance on how much an effect on QTc duration might be related to the risk of cardiac toxicity. For oncology products, the central tendency magnitude and proportion of outliers needs to be well defined to construct a label if the risk-benefit analysis leads to marketing approval. Clinical cardiac findings such as syncope, ventricular tachyarrhythmias, and other cardiac effects will be important in this analysis.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Dose finding in pediatric patients.

  G Henze
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  ABSTRACT: It is generally agreed that satisfactory safety and effectiveness of pharmaceutical products for children and adolescents have not yet been established. This applies in particular to anti-cancer drugs and even to those having successfully been used for many years in multidrug chemotherapy protocols for childhood cancer. For example, nephroblastoma or Wilms' tumor is one of the typical and frequent forms of childhood cancer occurring at a median age of about 3 years. Standard therapy for Wilms' tumor is the combination of vincristine and actinomycin D; survival is about 85%. For actinomycin D, the summary of product characteristics states that one contraindication is children aged below 6-12 months. If this would be considered and respected it would mean that a substantial proportion of children with Wilms' tumor would not be treated and thus a proven curative therapy would be withheld. The current situation in pediatrics is that off-label use has become a common practice: in private practice about 20% of prescriptions are off-label, in children's hospitals approximately 40%-50% with 50%-70% in pediatric oncology and more than 90% in neonatology (Conroy et al. 1999, 2000, 2003; Turner et al. 1996, 1998; McIntyre et al. 2000). These conditions are more or less tolerated by the authorities although they are beyond legality. The reason is that appropriate clinical trials like those in adults have not been conducted in children and drugs have therefore not been licensed.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Biometrical aspects of drug development.

  D Machin, S B Tan
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  ABSTRACT: Once the activity of a compound has been established in the laboratory (usually by use of experimental animals) the next stage of development is to bring this forward to humans in early-phase clinical trials. A pharmacokinetic study aims to establish an effective dosing regimen for the compound in order to reach concentrations within the therapeutic window as quickly as possible. The aim of the phase I trials is typically to determine a maximal safe dose with which more rigorous investigation of activity in a phase II trial can be conducted. This chapter deals with statistical issues related to the design of phase I studies.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: The applications of biomarkers in early clinical drug development to improve decision-making processes.

  J Kuhlmann
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  ABSTRACT: Selecting and evaluating biomarkers in drug discovery and early drug development can substantially shorten clinical development time or the time to reach a critical decision point in exploratory drug development. Critical decisions such as candidate selection, early proof of concept/principle, dose ranging, development risks, and patient stratification are based on the appropriate measurements of biomarkers that are biologically and/or clinically validated. The use of biomarkers helps to streamline clinical development by determining whether the drug is reaching and affecting the molecular target in humans, delivering findings that are comparable to preclinical data, and by providing a measurable endpoint that predicts desired or undesired clinical effects and will increase the success rate in the confirmatory stage of clinical development. Appropriateness of biomarkers depends on the stage of development, development strategy, and the nature of the medical indication. Even if a biomarker fails in the validation process there may be still a benefit of having used it. More knowledge about pathophysiology of the disease and the drug has been obtained. Different levels of validation exist at different development phases. Biomarkers are perhaps most useful in the early phase of clinical development when measurement of clinical endpoints may be too time-consuming or cumbersome to provide timely proof of concept or dose-ranging information. Examples of biomarkers are illustrated for the development of new drugs in variant cardiovascular, pulmonary, and CNS diseases.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Molecular imaging with PET--open questions?

  P A Schubiger
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  ABSTRACT: Molecular imaging has become a very popular term in medicine and can be interpreted in many different ways. It is argued that a correct definition should be 'in vivo imaging of biological processes with appropriate molecular probes'. The real challenge in molecular imaging therefore is the search for the 'optimal' molecular imaging probes. It is discussed that nuclear, optical and magnetic probes can be used. However, only PET probes have the high sensitivity to be applied generally. To develop PET probes efficiently, methods for the in vitro and in vivo characterization are discussed and alternatives compared. Some open questions with respect to the reliability of animal imaging and evaluation of the imaging data will be elucidated.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Can cell systems biology rescue drug discovery?

  E C Butcher
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  ABSTRACT: The focus of innovation in current drug discovery is on new targets, yet compound efficacy and safety in biological models of disease, not target selection, qualify drug candidates for the clinic. We consider a biology-driven approach to drug discovery based on screening compounds by automated response profiling in complex human cell systems-based disease models. Drug discovery through cell systems biology could significantly reduce the time and cost of new drug development.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: 68Ga-PET radiopharmacy: A generator-based alternative to 18F-radiopharmacy.

  H R Maecke, J P André
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  ABSTRACT: Positron emission tomography (PET) is becoming a dominating method in the field of molecular imaging. Most commonly used radionuclides are accelerator produced 11C and 18F. An alternative method to label biomolecules is the use of metallic positron emitters; among them 68Ga is the most promising as it can be produced from a generator system consisting of an inorganic or organic matrix immobilizing the parent radionuclide 68Ge. Germanium-68 has a long half-life of 271 days which allows the production of long-lived, potentially very cost-effective generator systems. A commercial generator from Obninsk, Russia, is available which uses TiO2 as an inorganic matrix to immobilize 68Ge in the oxidation state IV+. 68Ge(IV) is chemically sufficiently different to allow efficient separation from 68Ga(III). Ga3+ is redox-inert; its coordination chemistry is dominated by its hard acid character. A variety of mono- and bifunctional chelators were developed which allow immobilization of 68Ga3+ and convenient coupling to biomolecules. Especially peptides targeting G-protein coupled receptors overexpressed on human tumour cells have been studied preclinically and in patient studies showing high and specific tumour uptake and specific localization. 68Ga-radiopharmacy may indeed be an alternative to 18F-based radiopharmacy. Freeze-dried, kit-formulated precursors along with the generator may be provided, similar to the 99Mo/99mTc-based radiopharmacy, still the mainstay of nuclear medicine.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Fluorine-18 labeling methods: Features and possibilities of basic reactions.

  H H Coenen
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  ABSTRACT: Many experimental and established tracers make fluorine- 18 the most widely used radionuclide in positron emission tomography with an increasing demand for new or simpler 18F-labeling procedures. After a brief summary of the advantages of the nuclide and its major production routes, the basic features of the principal radiofluorination methods are described. These comprise direct electrophilic and nucleophilic processes, or in case of more complex molecules, the labeling of synthons and prosthetic groups for indirect built-up syntheses. While addressing the progress of no-carrier-added 18F-labeling procedures, the following chapters on more specific topics in this book are introduced. Emphasis is given to radiofluorination of arenes--especially with iodonium leaving groups. Examples of radiopharmaceutical syntheses are mentioned in order to illustrate strategic concepts of labeling with fluorine-18.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Experiences with dose finding in patients in early drug development: the use of biomarkers in early decision making.

  S R Sultana, S Marshall, J Davis, B H Littman
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  ABSTRACT: With the increasing cost and complexity of drug development, biomarkers will play an increasing role in the early phases. Biomarkers can be classified into target, mechanistic, or outcome with varying degrees of linkage to disease or treatment effect. They can be used to determine proof of concept by characterising the efficacy or safety profiles, or determining differentiation from any competitor drugs. PK/PD modelling of biomarker data for novel and marketed compounds can be used to predict outpatient dose response. Subsequent simulations may replace or reduce the size and cost of larger phase 2b outpatient studies. Two examples of biomarkers and PK/PD modelling used to characterise dose response are presented. Penile plethysmography (RigiScan Plus) in male erectile dysfunction and phenylephrine challenge urethral pressure in benign prostatic hyperplasia are used to reduce time and cost to reach major exploratory development decision points in these indications.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: The role of PET scanning in determining pharmacoselective doses in oncology drug development.

  P Price
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  ABSTRACT: Molecular imaging is the most sensitive and specific method for measuring in vivo molecular pathways in man. Its use in oncology has developed significantly over the last 5-10 years. Molecules can be labelled with positron emitting isotopes and the emitted radiation is detected using sensitive positron emission tomography (PET) cameras. It is now possible to measure in vivo and normal tissue pharmacokinetics of anti-cancer drugs and investigate their mechanism of action. Radiolabelling of tracers can be used to measure specific pharmacodynamic endpoints and target identification. Increasing evidence shows how these technologies, when added to early drug development, can rapidly reduce the time for entry into man and early identification of mechanisms of action. With the move towards more segmented markets and identification of specific subgroups, PET's use for noninvasive biomarkers will become in- creasingly important. However, much international effort between academia and industry is required with prioritisation of development of this technology.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Preventing postmarketing changes in recommended doses and marketing withdrawals.

  C Peck
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  ABSTRACT: Recent market withdrawals of prescription drug products have brought attention to premarketing safety research. Less known but related to some drug withdrawals are postmarketing dosage changes of newly marketed drugs, including both dosage reductions and increases. These events have serious effects on patients, manufacturers, and regulatory authorities. Most of these harmful events could be avoided by intensive employment of targeted clinical pharmacology investigations to optimize dosage prior to phase III testing and regulatory approval. In this paper, the frequency and implications of postmarketing dosing changes and market withdrawals are considered in light of approaches to preventing them.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Pharmacological prerequisites for PET ligands and practical issues in preclinical PET research.

  S M Ametamey, M Honer
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  ABSTRACT: The development of PET radiopharmaceuticals for the non-invasive imaging of cancerous lesions, brain receptors, transporters and enzymes started more than 25 years ago. But till today no established algorithms exist to predict the success of a PET radiopharmaceutical. PET radioligand development is a challenging endeavor and predicting the success of PET ligand can be an elusive undertaking. A large number of PET radiopharmaceuticals have been developed for imaging, but so far only a few have found application as imaging agents in vivo in humans. Typically, the potential compound selected for development usually has the desired in vitro characteristics but unknown in vivo properties. The purpose of this chapter is to highlight some of the pharmacological constraints and prerequisites. Interspecies difference in metabolism and mass effects are discussed with examples. Finally, some of the practical issues related to laboratory animal imaging using anesthetic agents are also presented.
  Ernst Schering Research Foundation workshop 02/2007;
• Article: Micro-reactors for PET tracer labeling.

  S Y Lu, V W Pike
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  ABSTRACT: Miniaturization of PET radiosynthesis devices (micro-reactors or microfluidic systems) is an emerging area that has the potential to deliver many advantages, such as more efficient use of hot-cell space for production of multiple radiotracers; use of less non-radioactive precursor for saving precious material and a reduced separation challenge; highly controlled, reproducible and reliable radiotracer production; and cheap, interchangeable, disposable and quality-assured radiochemistry processors. Several 'proof of principle' examples along with basics of micro-reactor flow control, mixing principle and design, and device fabrication are discussed in this chapter.
  Ernst Schering Research Foundation workshop 02/2007;