Imaging In Drug Development Research Articles

Role of Brain Imaging in Drug Development for Psychiatry.

Over the last decades, many brain imaging studies have contributed to new insights in the pathogenesis of psychiatric disease. However, in spite of these developments, progress in the development of novel therapeutic drugs for prevalent psychiatric health conditions has been limited. In this review, we discuss translational, diagnostic and methodological issues that have hampered drug development in CNS disorders with a particular focus on psychiatry. The role of preclinical models is critically reviewed and opportunities for brain imaging in early stages of drug development using PET and fMRI are discussed. The role of PET and fMRI in drug development is reviewed emphasizing the need to engage in collaborations between industry, academia and phase I units. Brain imaging technology has revolutionized the study of psychiatric illnesses, and during the last decade, neuroimaging has provided valuable insights at different levels of analysis and brain organization, such as effective connectivity (anatomical), functional connectivity patterns and neurochemical information that may support both preclinical and clinical drug development. Since there is no unifying pathophysiological theory of individual psychiatric syndromes and since many symptoms cut across diagnostic boundaries, a new theoretical framework has been proposed that may help in defining new targets for treatment and thus enhance drug development in CNS diseases. In addition, it is argued that new proposals for data-mining and mathematical modelling as well as freely available databanks for neural network and neurochemical models of rodents combined with revised psychiatric classification will lead to new validated targets for drug development.

PET Molecular Imaging in Drug Development: The Imaging and Chemistry Perspective.

Positron emission tomography with selective radioligands advances the drug discovery and development process by revealing information about target engagement, proof of mechanism, pharmacokinetic and pharmacodynamic profiles. Positron emission tomography (PET) is an essential and highly significant tool to study therapeutic drug development, dose regimen, and the drug plasma concentrations of new drug candidates. Selective radioligands bring up target-specific information in several disease states including cancer, cardiovascular, and neurological conditions by quantifying various rates of biological processes with PET, which are associated with its physiological changes in living subjects, thus it reveals disease progression and also advances the clinical investigation. This study explores the major roles, applications, and advances of PET molecular imaging in drug discovery and development process with a wide range of radiochemistry as well as clinical outcomes of positron-emitting carbon-11 and fluorine-18 radiotracers.

Antibody-Drug Conjugates for Cancer Therapy.

Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

Quantitative PET Imaging in Drug Development: Estimation of Target Occupancy.

Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies.

Live-Cell High Content Screening in Drug Development.

In the past decade, automated microscopy has become an important tool for the drug discovery and development process. The establishment of imaging modalities as screening tools depended on technological breakthroughs in the domain of automated microscopy and automated image analysis. These types of assays are often referred to as high content screening or high content analysis (HCS/HCA). The driving force to adopt imaging for drug development is the quantity and quality of cellular information that can be collected and the enhanced physiological relevance of cellular screening compared to biochemical screening. Most imaging in drug development is performed on fixed cells as this allows uncoupling the preparation of the cells from the acquisition of the images. Live-cell imaging is technically challenging, but is very useful for many aspects of the drug development pipeline such as kinetic studies of compound mode of action or to analyze the motion of cellular components. Most vendors of HCS microscopy systems offer the option of environmental chambers and onboard pipetting on their platforms. This reflects the wish and desire of many customers to have the ability to perform live-cell assays on their HCS automated microscopes. This book chapter summarizes the challenges and advantages of live-cell imaging in drug discovery. Examples of applications are presented and the motivation to perform these assays in kinetic mode is discussed.

Drug Discovery by Molecular Imaging and Monitoring Therapy Response in Lymphoma.

Molecular imaging allows a noninvasive assessment of biochemical and biological processes in living subjects. Treatment strategies for malignant lymphoma depend on histology and tumor stage. For the last two decades, molecular imaging has been the mainstay diagnostic test for the staging of malignant lymphoma and the assessment of response to treatment. This technology enhances our understanding of disease and drug activity during preclinical and clinical drug development. Here, we review molecular imaging applications in drug development, with an emphasis on oncology. Monitoring and assessing the efficacy of anti-cancer therapies in preclinical or clinical models are essential and the multimodal molecular imaging approach may represent a new stage for pharmacologic development in cancer. Monitoring the progress of lymphoma therapy with imaging modalities will help patients. Identifying and addressing key challenges is essential for successful integration of molecular imaging into the drug development process. In this review, we highlight the general usefulness of molecular imaging in drug development and radionuclide-based reporter genes. Further, we discuss the different molecular imaging modalities for lymphoma therapy and their preclinical and clinical applications.

Molecular imaging in drug development: Update and challenges for radiolabeled antibodies and nanotechnology.

Despite the significant advancement achieved in understanding the molecular mechanisms responsible for cancer transformation and aberrant proliferation, leading to novel targeted cancer therapies, significant effort is still needed to "personalize" cancer treatment. Molecular imaging is an emerging field that has shown the ability to characterize in vivo the molecular pathways present at the cancer cell level, enabling diagnosis and personalized treatment of malignancies. These technologies, particularly SPECT and PET also permit the development of novel radiotheranostic probes, which provide capabilities for diagnosis and treatment with the same agent. The small therapeutic index of most anticancer agents is a limitation in the drug development process. Incorporation of molecular imaging in clinical research may help in overcoming this limitation and favouring selection of patient populations most likely to achieve benefit from targeted therapy. This review will focus on two of the most advanced theranostic approaches with promising potential for application in the clinic: 1) therapeutic monoclonal antibodies which may be linked to a radionuclide for SPECT or PET imaging to guide cancer diagnosis, staging, molecular characterization, and assessment of the response to treatment and 2) multifunctional nanotechnology that allows image guided drug delivery through encapsulation of multiple therapeutic, targeting and imaging agents into a single nanoparticle. Porphysome, a liposome-like nanoparticle, is an example of a novel and promising application of nanotechnology for cancer diagnosis and treatment. These technologies have proven to be effective in preclinical models, warranting further clinical investigation to advance their application for the benefit of cancer patients.

Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Most of the known approved drugs comprise functionalized heterocyclic compounds as subunits. Among them, non-fluorescent quinazolines with four different substitution patterns are found in a variety of clinically used pharmaceuticals, while 4,5,7,8-substituted quinazolines and those displaying their own specific fluorescence, favourable for cellular uptake visualization, have not been described so far. Here we report the development of a one-pot synthetic strategy to access these 4,5,7,8-substituted quinazolines, which are fluorescent and feature strong antiviral properties (EC50 down to 0.6±0.1 μM) against human cytomegalovirus (HCMV). Merging multistep domino processes in one-pot under fully metal-free conditions leads to sustainable, maximum efficient and high-yielding organic synthesis. Furthermore, generation of artesunic acid–quinazoline hybrids and their application against HCMV (EC50 down to 0.1±0.0 μM) is demonstrated. Fluorescence of new antiviral hybrids and quinazolines has potential applications in molecular imaging in drug development and mechanistic studies, avoiding requirement of linkage to external fluorescent markers.

Potential Therapeutic Applications of Adenosine A2A Receptor Ligands and Opportunities for A2A Receptor Imaging.

Adenosine A2A receptors (A2A Rs) are highly expressed in the human striatum, and at lower densities in the cerebral cortex, the hippocampus, and cells of the immune system. Antagonists of these receptors are potentially useful for the treatment of motor fluctuations, epilepsy, postischemic brain damage, or cognitive impairment, and for the control of an immune checkpoint during immunotherapy of cancer. A2A R agonists may suppress transplant rejection and graft-versus-host disease; be used to treat inflammatory disorders such as asthma, inflammatory bowel disease, and rheumatoid arthritis; be locally applied to promote wound healing and be employed in a strategy for transient opening of the blood-brain barrier (BBB) so that therapeutic drugs and monoclonal antibodies can enter the brain. Increasing A2A R signaling in adipose tissue is also a potential strategy to combat obesity. Several radioligands for positron emission tomography (PET) imaging of A2A Rs have been developed in recent years. This review article presents a critical overview of the potential therapeutic applications of A2A R ligands, the use of A2A R imaging in drug development, and opportunities and limitations of PET imaging in future research.

Childhood extracranial neoplasms: the role of imaging in drug development and clinical trials.

Cancer is the leading cause of death in children older than 1 year of age and new drugs are necessary to improve outcomes. Imaging is crucial to the drug development process and assessment of therapeutic response. In adults, tumours are often assessed with CT using size criteria. Unfortunately, techniques established in adults are not necessarily applicable in children due to differing pathophysiology, ability to cooperate and increased susceptibility to ionising radiation. MRI, in particular quantitative MRI, has to date not been fully utilised in children with extracranial neoplasms. The specific challenges of imaging in children, the potential for functional imaging techniques to inform upon and their inclusion in clinical trials are discussed.

Mass spectrometry imaging in drug development.

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTMass Spectrometry Imaging in Drug DevelopmentAnna Nilsson†, Richard J. A. Goodwin‡, Mohammadreza Shariatgorji†, Theodosia Vallianatou†, Peter J. H. Webborn‡, and Per E. Andrén*†View Author Information† Biomolecular Imaging and Proteomics, National Center for Mass Spectrometry Imaging, Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591 BMC, 75124 Uppsala, Sweden‡ Drug Safety & Metabolism, Innovative Medicines, AstraZeneca, Darwin Building 310, Cambridge Science Park, Milton Road, Cambridge, Cambridgeshire CB4 OWG, U.K.*E-mail: [email protected]. Phone +46−18 471 7206. Mobile: +46−70 167 9334.Cite this: Anal. Chem. 2015, 87, 3, 1437–1455Publication Date (Web):December 19, 2014Publication History Published online14 January 2015Published inissue 3 February 2015https://doi.org/10.1021/ac504734sCopyright © 2014 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views4800Altmetric-Citations130LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (2 MB) Get e-AlertsSUBJECTS:Central nervous system,Ionization,Ions,Metabolism,Pharmaceuticals Get e-Alerts

Imaging in drug development.

Imaging has played an important part in the diagnosis of disease and development of the understanding of the underlying disease mechanisms and is now poised to make an impact in the development of new pharmaceuticals. This chapter discusses the underlying technologies that make the field ready for this challenge. In particular, the potentials of magnetic resonance imaging and functional magnetic resonance imaging are outlined, including the new methods developed to provide additional information from the scans carried out. The field of nuclear medicine has seen a rapid increase in interest as advances in radiochemistry have enabled a wide range of new radiotracers to be synthesised.

E-Learning with EMBS: Employing Medical Imaging in Drug Development [Continuing Education

The development of novel drugs is a lengthy process that requires years of preclinical and clinical research and many steps to ensure that the developed compound can be administered with minimal risk to patients. Drug effectiveness was traditionally assessed based on well-established clinical end points. However, secondary surrogate end points can also be assessed on the basis of biological markers quantified using imaging that serve as direct indicators of the drug's therapeutic efficiency. Compared to primary end points, biomarkers are expected to provide a shorter evaluation process without compromising the safety and efficiency of the developed drug. Modern imaging technologies enable multidimensional and multiparameter data visualization. As the spatial and temporal resolution has improved with newer imaging technologies, various modalities have been used to monitor substrate and protein dynamics and study the progression of therapy delivery in real time. For example, imaging data can provide the basis for the mathematical modeling of protein kinetics and biochemical signaling networks. While imaging modalities are now applied to provide secondary end points in some therapeutic areas, it is desirable to include imaging for end-point assessment in preclinical investigations by exploring models designed to report the activity of selected biomarkers that are detectable by certain imaging modalities. Moreover, with the advent of molecular probes, imaging will aid in not only visualizing gross anatomical structures but also visualizing cellular substructures and monitoring molecular dynamics. To complement the available knowledge on the scientific and operational use of medical imaging in drug development, the IEEE Engineering in Medicine and Biological Society (EMBS) has launched a recent education initiative to convey a series of tutorials on this topic to cater to specialists in the field as well as others interested in the concepts, methodologies, and applications. The educational material consists of slide presentations narrated by Prof. Mats Bergstroem. He has more than 30 years of experience in medical imaging and more than ten years of experience in the pharmaceutical industry.

31IN - The Role of Molecular Imaging in Early Drug Development

ABSTRACT Molecular cancer biology revealed an ever-increasing number of disease regulating intracellular and extracellular tumour targets. These new insights in the pathogenesis of tumor cells have lead to the development of a broad range of targeted therapeutic agents. In cancer, few targets have been identified that cover all types of cancer from a given site of origin. Hence, patient selection by molecular characterization of disease subtype in an individual patient becomes increasingly important in order to avoid unnecessary toxicity, improve patient outcome and reduce the costs for clinical trials. Biomarkers are objectively measured indicators of biological and pathogenic processes and can be used to predict patient outcome (regardless of therapy), to predict response to specific therapies and for response assessment (monitoring). The advantages of imaging biomarkers over those that require a biopsy sample include non-invasiveness, the ability to quantify cellular targets for the entire disease burden, and thereby to avoid the sampling error that can occur with heterogeneous receptor expression and the potential for serial studies of the in vivo effects of a drug on the target. In terms of drug development, predictive imaging biomarkers have a high potential for reducing costs of clinical trials, as they can be used for enriching patient selection by assessing drug targeting and/or early-on response prediction. The scope of this presentation is to highlight the potential of molecular imaging in drug development, illustrated by examples where molecular imaging has been implemented in clinical trials. Disclosure The author has declared no conflicts of interest.

Imaging in drug development: will it deliver on the promise of personalised medicine?

Over recent years, many new techniques have been applied to drug development in an effort to provide safer and more effective therapies to the patient. In addition, the intense competition between commercial interests continues to drive this search for new and effective technologies. The common goal is the provision of personalised medicine: an approach based on our growing understanding of the molecular basis of disease.

Translational Molecular Imaging in Drug Development: Current Status and Challenges

Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. In the past decade, there has been sufficient experience with specifically targeted therapeutic or diagnostic imaging agents that we must begin moving them from bench to bedside. However, crucial prerequisites for the development of safe pre-clinical protocols in molecular imaging research are needed through suitable large animal models since most of previous experiments were carried out on rodents. This review is focus on the translational molecular imaging research on drug development and radiopharmaceutical drug development, animal model selection, experimental design, the obstacle and future challenges of translational molecular imaging.

How have developments in molecular imaging techniques furthered schizophrenia research?

Molecular imaging techniques have led to significant advances in understanding the pathophysiology of schizophrenia and contributed to knowledge regarding potential mechanisms of action of the drugs used to treat this illness. The aim of this article is to provide a review of the major findings related to the application of molecular imaging techniques that have furthered schizophrenia research. This article focuses specifically on neuroreceptor imaging studies with PET and SPECT. After providing a brief overview of neuroreceptor imaging methodology, we consider relevant findings from studies of receptor availability, and dopamine synthesis and release. Results are discussed in the context of current hypotheses regarding neurochemical alterations in the illness. We then selectively review pharmacological occupancy studies and the role of neuroreceptor imaging in drug development for schizophrenia.

Noninvasive structural, functional, and molecular imaging in drug development

Modern drug research is mechanism-based and the development of disease modifying therapies involves the identification of molecular key players in the pathological cascade. Today, noninvasive imaging tools enable the visualization and quantitative assessment of the expression of molecular targets, of their interaction with potential ligands, as well as of the functional consequence of this interaction at a molecular (e.g. activation of signaling cascades), cellular, metabolic, physiological, and morphological level in a temporo-spatially resolved manner. The ability to gather such information from the intact organism with all regulatory processes in place renders imaging highly attractive for the biomedical researcher and for the drug developer in particular. Molecular imaging is potentially capable of providing this information. Today, proof-of-principle has been established that imaging is in fact adding value to the drug discovery and development processes. Numerous studies have used structural and functional imaging readouts to document therapy efficacy, mainly during lead optimization. Similarly, major efforts have been devoted to the development and evaluation of imaging biomarkers that might serve as early readouts for therapy response with the potential of being used in the clinical drug evaluation thereby facilitating translational research. In this contribution, we illustrate the role and potential of imaging in modern drug discovery and development with selected examples. Yet, despite its huge potential the impact of imaging on drug discovery has been modest in the past; potential reasons will be discussed. Nevertheless, noninvasive imaging methods are rapidly evolving and it is beyond doubt that their importance for biomedical research will increase.

Molecular imaging in drug development

Molecular imaging can allow the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development, which could aid decisions to select candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail. Here, with an emphasis on oncology, we review the applications of molecular imaging in drug development, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.

Form to function: current and future roles for atherosclerosis imaging in drug development

There is a pressing need for robust imaging markers to assist in the development of drugs for the treatment of atherosclerosis. Conventional imaging methods provide quantitative and morphological data but may be inadequate for assessing a new generation of therapies that modify plaque biology directly. Here, we compare the main imaging modalities used to image atherosclerosis in the clinical-trial setting, and assess their ability to predict clinical outcomes for a given sample size. We consider how emerging molecular and cellular imaging techniques could offer the possibility to quantify changes in biological function at the level of the plaque, even without gross structural change.