Positron emission tomography molecular imaging for drug development

Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development.     

Application of cardiac molecular imaging using positron emission tomography in evaluation of drug and therapeutics for cardiovascular disorders

The incidence of cardiovascular disease is increasing with the aging population. This has stimulated a need for innovative means to evaluate and develop therapeutic strategies intended to improve patient care. Positron emission tomography (PET) imaging is an advanced nuclear imaging technology. The advantage of PET over other non-invasive imaging modalities is its ability to accurately measure tissue concentrations of specific radiolabeled compounds. These radioligands can be used as molecular probes to quantify physiological processes and the effects of therapy. Molecular imaging with PET has been applied to evaluate new and established drugs and therapies, as well as their effects on physiological parameters. New radiolabeled receptor ligands will also allow in vivo pharmacokinetic studies following drug treatment, yielding insights into drug delivery, optimal drug occupancy, and mechanism of action at the receptor level. These exciting tissue pharmacokinetic data could revolutionize evaluation of drug therapies in cardiovascular diseases. In addition, serial evaluations of these processes are now possible in both animals and humans permitting sensitive means to evaluate disease progression and therapies. New tools for imaging such as PET/CT and small animal PET broaden the potential of PET in drug evaluation. This review will describe the accuracy of PET as a non-invasive modality to quantify various parameters, and the application of PET in evaluating new and established therapies. This paper will also review the application of receptor ligand imaging and the principles of using surrogate physiological end-points in early drug development and evaluation.     

Has molecular and cellular imaging enhanced drug discovery and drug development?

A great many efforts have been made to accelerate the drug discovery and development process, which is extremely time and money consuming. Recently developed molecular imaging has many significant advantages over conventional methods for examining molecular pathways and obtaining pharmacokinetic, pharmacodynamic and mechanistic information. This review briefly summarizes various molecular and cellular imaging techniques and discusses several important applications of molecular and cellular imaging in drug discovery and development, which include: (i) measurement of pharmacodynamic endpoints by imaging metabolism and proliferation, imaging angiogenic parameters, and imaging a particular pathway or downstream target; (ii) evaluation of pharmacokinetics; and (iii) imaging therapeutic gene expression with relevance to gene therapy. Molecular imaging is becoming more widely used as a non-invasive tool for drug discovery and drug screening. Further refinements in imaging techniques, optimization of imaging probes and collaborative efforts will be needed to fully realise the vast potential of molecular imaging techniques in discovering and developing new drugs.     

Imaging as a tool in drug development

Medical imaging has experienced a huge increase in exploratory technologies over the past 20 to 30 years. From drug discovery to drug development to routine clinical practice, the advent of functional imaging is about to revolutionize both medicine and pharmaceutical drug development. Currently, a number of technologies are in competition. Positron emission tomography (PET) and magnetic resonance imaging (MRI) have advanced furthest as useful adjuncts to clinical drug development, even though data from both remain, at best, biomarkers that alone will not suffice for regulatory approval. However, the high-risk proof-of-concept and early proof-of-efficacy trial programs can be accelerated with judicious use of PET or MRI. The U.S. Food and Drug Administration (FDA) is currently working to establish guidelines for these new imaging methods, which might accelerate drug development and improve treatment of individual patients.     

Optical imaging in drug discovery and diagnostic applications

Optical imaging combines a variety of different diagnostic modalities which have shown great promise for biomedical imaging and as a tool in drug discovery. Several different principles to identify and characterize fundamental processes at the organ, tissue, cellular and molecular level have been exploited, supported by the design of novel imaging agents and biomolecular reporter systems. New optical imaging procedures will contribute considerably to the improvement of the knowledge of disease processes and the more efficient evaluation of drug effects in living laboratory animals. They may also find new diagnostic and therapeutic applications in human clinical practices. These techniques can be used in the field of molecular imaging to allow both visualization and quantification of molecular events associated with disease in a non-invasive and radiation-free manner using relatively simple equipment. The different aspects of imaging instrumentation and methods; the achievements in synthesis and evaluation of novel imaging agents and biochemical reporters; as well as the opportunities of optical imaging in drug delivery, drug discovery and imaging diagnostics will be discussed in this review article.     

Molecular imaging with SPECT as a tool for drug development

Molecular imaging techniques are increasingly being used as valuable tools in the drug development process. Radionuclide-based imaging modalities such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have proven to be useful in phases ranging from preclinical development to the initial stages of clinical testing. The high sensitivity of these imaging modalities makes them particularly suited for exploratory investigational new drug (IND) studies as they have the potential to characterize in vivo pharmacokinetics and biodistribution of the compounds using only a fraction of the intended therapeutic dose (microdosing). This information obtained at an early stage of clinical testing results in a better selection among promising drug candidates, thereby increasing the success rate of agents entering clinical trials and the overall efficiency of the process. In this article, we will review the potential applications of SPECT imaging in the drug development process with an emphasis on its applications in exploratory IND studies.     

Early in vivo testing to assess new therapeutic interventions in CF patients

New therapeutic strategies are targeting correction of the basic defect in cystic fibrosis (CF) disease. In fact, completion of the first successful clinical drug trials now signals the start of a new era in CF therapy. Many promising drug candidates are emerging into the clinical drug pipeline. However, their translation from the bench to the bed side is challenged by the lack of accurate and reliable biomarker assays that allow testing for their clinical efficiency and safety in early clinical trials. It is surprising that despite the availability of modern equipment and technologies relatively little effort has been directed towards innovative approaches to exploit our pathophysiological understanding of CF disease for the design of novel assays that allow in vivo assessment of CFTR dysfunction as the measurable correlate of the basic defect of CF disease. This lack of adequate outcome measure is now gaining increased attention, and first studies are being initiated to screen larger CF patient cohorts for biological markers that can be used as a potential measure of drug response. This paper reviews currently available in vivo tests, highlighting new methods and their potential use as early in vivo markers for therapeutic investigations. Finally, key criteria of the validation process that needs to be addressed before new biomarker assays can be introduced into clinical trials are discussed.     

Non-invasive imaging in experimental medicine for drug development

Clinical imaging offers a range of methods for the support of drug development that are able to address major questions related to target validation and molecule biodistribution, target interactions and pharmacodynamics. Here we review recent innovative applications of positron emission tomography (PET) and magnetic resonance imaging (MRI). New approaches to human target validation exploring MRI or PET biomarker changes related to allelic variation at candidate target loci can contribute to human target validation. PET molecular imaging can define molecule biodistribution directly and, if an appropriate, target-specific radioligand is available, be employed in small experimental medicine studies to provide plasma pharmacokinetic-target occupancy data to guide dose selection. An enlarging range of imaging biomarkers for pharmacodynamic studies is enabling imaging experimental medicine studies to assess the potential efficacy of new therapeutic molecules. Integration of these approaches promises improvements in therapeutic molecule differentiation and may contribute in ways that would improve the value proposition for use of a new drug through patient stratification.     

The role of positron emission tomography in the discovery and development of new drugs; as studied in laboratory animals.

Drug discovery and development is time consuming and a costly procedure. The challenges for the pharmaceutical industry range from the evaluation of potential new drug candidates, the determination of drug pharmacokinetics/pharmacodynamics, the measurement of receptor occupancy as a determinant of drug efficacy, and the pharmacological characterisation of mechanisms of action. Positron emission tomography (PET) is a powerful quantitative imaging technique for looking at biochemical pathways, molecular interactions, drug pharmacokinetics and pharmacodynamics. Recent advances in emission tomography, particularly the development of small animal PET scanners, image reconstruction and animal models of disease have led to the development of extremely sensitive and specific tools for imaging biochemical processes in vivo, therefore representing a new means of providing information for drug development and evaluation. Many human genes have a related mouse gene, allowing mice to be used as a platform for mimicking human disease, using knock-out and knock-in gene technology. Consequently PET imaging of rodents is emerging as a cost effective means of screening new pharmaceuticals and decreasing the time required for new drug development.     

Image-guided nanosystems for targeted delivery in cancer therapy

Current challenges in early detection, limitations of conventional treatment options, and the constant evolution of cancer cells with metastatic and multi-drug resistant phenotypes require novel strategies to effectively combat this deadly disease. Nanomedical technologies are evolving at a rapid pace and are poised to play a vital role in diagnostic and therapeutic interventions - the so-called "theranostics" - with potential to advance personalized medicine. In this regard, nanoparticulate delivery systems can be designed with tumor seeking characteristics by utilizing the inherent abnormalities and leaky vasculature of solid tumors or custom engineered with targeting ligands for more specific tumor drug targeting. In this review we discuss some of the recent advances made in the development of multifunctional polymeric nanosystems with an emphasis on image-guided drug and gene delivery. Multifunctional nanosystems incorporate variety of payloads (anticancer drugs and genes), imaging agents (optical probes, radio-ligands, and contrast agents), and targeting ligands (antibodies and peptides) for multi-pronged cancer intervention with potential to report therapeutic outcomes. Through advances in combinatorial polymer synthesis and high-throughput testing methods, rapid progress in novel optical/radiolabeling strategies, and the technological breakthroughs in instrumentation, such as hybrid molecular and functional imaging systems, there is tremendous future potential in clinical utility of theranostic nanosystems.     

Development and applications of photo-triggered theranostic agents

Theranostics, the fusion of therapy and diagnostics for optimizing efficacy and safety of therapeutic regimes, is a growing field that is paving the way towards the goal of personalized medicine for the benefit of patients. The use of light as a remote-activation mechanism for drug delivery has received increased attention due to its advantages in highly specific spatial and temporal control of compound release. Photo-triggered theranostic constructs could facilitate an entirely new category of clinical solutions which permit early recognition of the disease by enhancing contrast in various imaging modalities followed by the tailored guidance of therapy. Finally, such theranostic agents could aid imaging modalities in monitoring response to therapy. This article reviews recent developments in the use of light-triggered theranostic agents for simultaneous imaging and photoactivation of therapeutic agents. Specifically, we discuss recent developments in the use of theranostic agents for photodynamic-, photothermal- or photo-triggered chemotherapy for several diseases.     

Vulnerable plaque and inflammation: potential clinical strategies

Although enormous progress has been made in the prevention and treatment of cardiovascular disease, it still remains the leading cause of death worldwide. During the last decades, advances in the understanding of the pathophysiology of vulnerable plaque progression, coupled with novel diagnostic and therapeutic approaches, created a new opportunity for progress against cardiovascular disease. It has been demonstrated that inflammation, implicated in all stages of atherosclerosis, is an integral part of vulnerable plaque development and progression, leading eventually to plaque instability. Thus, new diagnostic modalities have been proposed for the detection of local plaque inflammation. Moreover, treatments such as stenting, photodynamic therapy, and novel pharmaceutical agents are under consideration as methods to stabilize the vulnerable plaques by inhibiting inflammation. This review provides an overview of the inflammatory process leading to atherosclerotic cardiovascular disease and the potential clinical strategies that may substantially decrease the incidence of events. We will mention the major impact of local and systemic inflammation on plaque advancing and destabilization, the imaging techniques for early detection of vulnerable plaques and the potential therapeutic strategies.     

PET and SPECT exploration of central monoaminergic transporters for the development of new drugs and treatments in brain disorders

Membrane and vesicular monoaminergic transporters, responsible for the homeostasis of neurotransmitter pools at nerve endings, are very involved in the physiology and diseases of central nervous system. Recent progresses of cerebral molecular imaging using SPECT and PET methods allow the extend of in vivo exploration of these transporters. For this aim, an increasing number of radiopharmaceuticals labelled with [123I], [99mTc], [11C] or [18F] have been developed such as cocaine derivatives for the DAT, compounds from the diphenyl sulfide family for the SERT, and dihydrotetrabenazine derivatives for the VMAT2. These functional imaging methods can be very useful in several neurological and psychiatric disorders which involve the monoaminergic neurotransmission systems such as Parkinson's disease, ADHD, depression and autism. For example, the DAT is a specific index of the density of dopaminergic endings which progressively degenerate in Parkinson's disease. In vivo exploration of this transporter can therefore be a relevant way (i) to realize an early detection of the loss of dopaminergic neurons, (ii) to assess the progression of the disease, (iii) to validate and improve the efficacy of new therapeutic strategies such as neuroprotection and neuroreparation. In all, the extend of in vivo exploration of monoamine transporters will allow great progress for (1) knowledge of physiopathological mechanisms of brain disorders, (2) early diagnosis of cerebral dysfunctions, allowing early use of new therapies, (3) selection of homogenous classes of subjects for therapeutic assays, (4) objectiveness of drug-molecular target interaction, (5) follow-up of disease evolution and treatment.     

Multimodal clinical imaging to longitudinally assess a nanomedical anti-inflammatory treatment in experimental atherosclerosis

Atherosclerosis is an inflammatory disease causing great morbidity and mortality in the Western world. To increase the anti-inflammatory action and decrease adverse effects of glucocorticoids (PLP), a nanomedicinal liposomal formulation of this drug (L-PLP) was developed and intravenously applied at a dose of 15 mg/kg PLP to a rabbit model of atherosclerosis. Since atherosclerosis is a systemic disease, emerging imaging modalities for assessing atherosclerotic plaque are being developed. (18)F-Fluoro-deoxy-glucose positron emission tomography and dynamic contrast enhanced magnetic resonance imaging, methods commonly used in oncology, were applied to longitudinally assess therapeutic efficacy. Significant anti-inflammatory effects were observed as early as 2 days that lasted up to at least 7 days after administration of a single dose of L-PLP. No significant changes were found for the free PLP treated animals. These findings were corroborated by immunohistochemical analysis of macrophage density in the vessel wall. In conclusion, this study evaluates a powerful two-pronged strategy for efficient treatment of atherosclerosis that includes nanomedical therapy of atherosclerotic plaques and the application of noninvasive and clinically approved imaging techniques to monitor delivery and therapeutic responses. Importantly, we demonstrate unprecedented rapid anti-inflammatory effects in atherosclerotic lesions after the nanomedical therapy.     

Measurement of renal function in patients with chronic kidney disease

Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease.     

Development of radiotracers for oncology--the interface with pharmacology

There is an increasing role for positron emission tomography (PET) in oncology, particularly as a component of early phase clinical trials. As a non-invasive functional imaging modality, PET can be used to assess both pharmacokinetics and pharmacodynamics of novel therapeutics by utilizing radiolabelled compounds. These studies can provide crucial information early in the drug development process that may influence the further development of novel therapeutics. PET imaging probes can also be used as early biomarkers of clinical response and to predict clinical outcome prior to the administration of therapeutic agents. We discuss the role of PET imaging particularly as applied to phase 0 studies and discuss the regulations involved in the development and synthesis of novel radioligands. The review also discusses currently available tracers and their role in the assessment of pharmacokinetics and pharmacodynamics as applied to oncology.     

Silica nanoparticles as promising drug/gene delivery carriers and fluorescent nano-probes: recent advances

The application of nanotechnology to biomedical research is expected to have a major impact leading to the development of new types of diagnostic and therapeutic tools. One focus in nanobiotechnology is to develop safe and efficient drug/gene delivery vehicles. Research into the rational delivery and targeting of pharmaceutical, therapeutic and diagnostic agents is at the forefront of projects in nanomedicine. Silica, as a major and natural component of sand and glass, is a versatile material due to the variety of available chemical and physical modifications that are available, and recently have been widely applied in nanobiotechnology as drug/gene carriers or fluorescent nano-probes. The goal of this brief review is to illustrate selected examples of various functionalized silica nanoparticles as drug/gene delivery systems that have been applied to the arenas of human disease therapy or detection (molecular and cellular imaging).     

Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development

The realisation that new chemical entities under development as drug candidates fail in three of four cases in clinical trials, together with increased costs and increased demands of reducing preclinical animal experiments, have promoted concepts for improvement of early screening procedures in humans. Positron emission tomography (PET) is a non-invasive imaging technology, which makes it possible to determine drug distribution and concentration in vivo in man with the drug labelled with a positron-emitting radionuclide that does not change the biochemical properties. Recently, developments in the field of rapid synthesis of organic compounds labelled with positron-emitting radionuclides have allowed a substantial number of new drug candidates to be labelled and potentially used as probes in PET studies. Together, these factors led to the logical conclusion that early PET studies, performed with very low drug doses—PET-microdosing—could be included in the drug development process as one means for selection or rejection of compounds based on performance in vivo in man. Another important option of PET, to evaluate drug interaction with a target, utilising a PET tracer specific for this target, necessitates a more rapid development of such PET methodology and validations in humans. Since only very low amounts of drugs are used in PET-microdosing studies, the safety requirements should be reduced relative to the safety requirements needed for therapeutic doses. In the following, a methodological scrutinising of the concept is presented. A complete pre-clinical package including limited toxicity assessment is proposed as a base for the regulatory framework of the PET-microdosing concept.