Measuring receptor occupancy with PET

Many physiological and biochemical measurements can be performed noninvasively in humans with modern imaging techniques like magnetic resonance imaging (MRI), positron emission tomography (PET) or single-photon emission computed tomography (SPECT). This review focuses on the monitoring of drug-receptor interactions in patients and healthy volunteers with PET. Such studies depend on the availability of a suitable radioligand; they are already possible for classical and atypical neuroleptics, anxiolytics, antidepressants, anticholinergics, antihistamines, antiepileptics, beta-blockers and hypnotic drugs. In Phase I-II human studies, measurements of plasma pharmacokinetics can be combined with images of receptor occupancy and be quantitatively related to pharmacologic effects which are induced in the same subjects. Optimal dosing schedules can be defined and valuable information for the design of Phase III studies can be acquired. Moreover, the effect of interventions (e.g. change of dose, additional medication) can be predicted. Medical imaging techniques will play an increasing role in clinical pharmacology and allow well-informed go/no-go decisions in future 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.     

Nuclear imaging of inflammation in neurologic and psychiatric disorders

Cerebral inflammation is a common phenomenon during the progression of neurodegenerative diseases. In general, neurodegenerative diseases have unpredictable clinical courses and timely effective treatment is not available. For effective clinical trials on new drugs, suitable surrogate markers to monitor disease progression are required. The extent of cerebral inflammation could be such a surrogate marker. Nuclear imaging techniques, like positron emission tomography (PET) and single photon emission computed tomography (SPECT), have been applied to monitor inflammatory processes in patients. Neuroinflammation is accompanied by a variety of physiological changes, such as changes in cerebral glucose metabolism and perfusion, cyclooxygenase-2 overexpression and microglia activation. Nuclear imaging has utilized these physiological changes to visualize the inflammatory process in various chronic or acute neurodegenerative diseases. Expression of the peripheral benzodiazepine receptor in activated microglia proved a suitable specific marker to detect neuroinflammation. Currently, radiolabeled COX-2 inhibitors are under investigation for this purpose. The causative of neuroinflammation is often unknown, but the herpes simplex virus (HSV), for example, has been implicated in several neurodegenerative diseases. Recently, antiviral agents and antibiotics have been prepared that might be applicable to discriminate specific viral or bacterial infections. These radiolabeled compounds could also be used to monitor the drug pharmacokinetics noninvasively with PET. This review summarizes the progress that has been made in nuclear imaging of neuroinflammation in,neuropsychiatric diseases.     

Use of positron emission tomography in anticancer drug development

Positron emission tomography (PET) is increasingly being used in anticancer drug development. The technique is applicable to studies of drug delivery, and where specific probes are available, to provide pharmacodynamic readouts noninvasively in patients. Mathematical modeling of the imaging data enhances the quality of information that is obtained from such studies. This section provides a review of the PET methodologies that have been used for the development of new cancer therapies. Other than imaging of radiolabeled drugs, PET modeling has found extensive application in studies with 2-[¹¹C]thymidine, [¹⁸F]fluorodeoxyglucose, H₂ ¹⁵O, C¹⁵O, and receptor ligands.     

Biomedical imaging in pharmacology with nuclear medical imaging methodologies: positron emission tomography (PET) and single photon emission computed tomography (SPECT)

The nuclear imaging technologies, positron emission tomography (PET) and single photon emission computed tomography (SPECT), have the power to non-invasively obtain dynamic and real-time information on the in vivo behaviors of radiolabeled molecules not only in humans but also in experimental animals. Thus, PET and SPECT can image molecular interactions of biological processes in vivo directly and reveal biological phenomena that are hidden from view. Furthermore, these imaging procedures also can be repeatedly performed before and after interventions, thereby allowing each subject to be used as its own control. In these studies, the radiolabeled compounds used as imaging probes for non-invasive assays of biochemical processes should have defined in vivo behaviors that can provide valuable information on the physiological and pharmacological processes. This paper describes the principle of the nuclear medical imaging systems, rational design of radiolabeled imaging probes, and the application to in vivo investigation of the change of various neurotransmission systems under disease and drug treatment. The efficient utilization of these nuclear medical imaging technologies will accelerate biomedical studies and drug development.     

PET imaging in clinical drug abuse research

Over the last two decades, SPECT (single photon emission computed tomography) and especially PET (positron emission tomography) have proven increasingly effective imaging modalities in the study of human psychopharmacology. Abusing populations can be studied at multiple times after abstinence begins, to give information about neurochemical and physiological adaptations of the brain during recovery from addiction. Individual human subjects can be studied using multiple positron labeled radiotracers, so as to probe more than one facet of brain function. PET and SPECT have been used to help our understanding of many aspects of the pharmacokinetics and pharmacodynamics of abused drugs, and have made valuable contributions in terms of drug mechanisms, drug interactions (e.g. cocaine and alcohol) and drug toxicities. They have also been employed to study the acute effects of drugs on populations of active drug abusers and of normal controls, and to evaluate the neurochemical consequences of candidate therapies for drug abuse. A particularly productive strategy has been the use of PET in conjunction with neuropsychological testing of subjects, to allow correlation of imaging data with uniquely human aspects of the effects of drugs, such as euphoria and craving.     

Positron emission tomography (PET): Expanding the horizons of oncology drug development

Positron emission tomography (PET) allows three-dimensional quantitative determination of the distribution of radioactivity permitting measurement of physiological, biochemical, and pharmacological functions at the molecular level. Until recently, no method existed to directly and noninvasively assess transport and metabolism of neoplastic agents as a function of time in various organs as well as in the tumor. Standard preclinical evaluation of potential anticancer agents entails radiolabeling the agent, usually with tritium or ¹⁴C, sacrifice experiments, and high-performance liquid chromatography (HPLC) analysis to determine the biodistribution and metabolism in animals. Radiolabeling agents with positron-emitting radionuclides allows the same information to be obtained as well as in vivo pharmacokinetic (PK) data by animal tissue and plasma sampling in combination with PET scanning. In phase I/II human studies, classic PK measurements can be coupled with imaging measurements to define an optimal dosing schedule and help formulate the design of phase III studies that are essential for drug licensure [1]. Many of the novel agents currently in development are cytostatic rather than cytotoxic and therefore, the traditional standard endpoints in phase I and II studies may no longer be relevant. The use of a specialized imaging modality that allows PK and pharmacodynamic (PD) evaluation of a drug of interest has been proposed to permit rapid and sensitive assessment of the biological effects of novel anticancer agents. The progress to date and the challenges of incorporating PET technology into oncology drug development from the preclinical to clinical setting are reviewed in this article.     

PET studies with carbon-11 radioligands in neuropsychopharmacological drug development.

A basic problem in the discovery and development of novel drugs to be used in the treatment of neurological and psychiatric disorders is the absence of relevant in vitro or in vivo animal models that can yield results which can be extrapolated to man. Drug research now benefits from the fast development of functional imaging techniques such as positron emission tomography (PET) which trace radiolabelled molecules directly in the human brain. PET uses molecules that are labelled with short-lived radionuclides and injected intravenously into experimental animals, human volunteers or patients. The most frequent approach is to study how an unlabelled drug inhibits specific binding of a well characterised selective PET radioligand. The alternative direct approach is to radiolabel a new potential drug and to trace its uptake, anatomical distribution and binding in brain. Furthermore, the effects of a novel drug on physiological-biochemical parameters, such as glucose metabolism or blood flow, can also be assessed. The demonstration of quantitative relationships between drug binding in vivo and drug effects in patients is used to validate targets for drug action, to correlate pharmacological and physiological effects, and to optimise clinical treatment.     

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.     

Receptor Occupancy Imaging Studies in Oncology Drug Development

The selection of therapeutic dose for the most effective treatment of tumours is an intricate interplay of factors. Molecular imaging with positron emission tomography (PET) or single–photon emission computed tomography (SPECT) can address questions central to this selection: Does the drug reach its target? Does the drug engage with the target of interest? Is the drug dose sufficient to elicit the desired pharmacological effect? Does the dose saturate available target sites? Combining functional PET and SPECT imaging with anatomical imaging technologies such as magnetic resonance imaging (MRI) or computed tomography (CT) allows drug occupancy at the target to be related directly to anatomical or physiological changes in a tissue resulting from therapy. In vivo competition studies, using a tracer amount of radioligand that binds to the tumour receptor with high specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Including imaging studies in early drug development can aid with dose selection and suggest improvements for patient stratification to obtain higher effective utility from a drug after approval. In this review, the potential value of including translational receptor occupancy studies and molecular imaging strategies early on in drug development is addressed.     

Fundamentals of positron emission tomography and applications in preclinical drug development

Positron emission tomography (PET) is a nuclear imaging technique that can dynamically image trace amounts of positron-labeled radiopharmaceuticals in vivo. Tracer concentrations can be determined quantitatively, and by application of appropriate tracer kinetic models, the rates of a wide range of different biological processes can be measured noninvasively in humans. PET has been used as a research tool for more than 25 years and has also found clinical applications, particularly in oncology, neurological disorders, and cardiovascular disease. Recently, there has been tremendous interest in applying PET technology to in vivo small-animal imaging. Significant improvements in the imaging technology now permit a wide range of PET studies in mice and rats, using compact, relatively low-cost, dedicated small-animal PET scanners. This article reviews the fundamental basis of PET imaging and discusses the development of small-animal PET scanners and their possible application in preclinical drug development.     

PET and SPECT imaging of the opioid system: receptors, radioligands and avenues for drug discovery and development

As we celebrate the bicentennial of the isolation of morphine by Sertürner, opioids continue to dominate major sectors of the analgesic market worldwide. The pharmaceutical industry stands to benefit greatly from molecular imaging in preclinical and early clinical trials of new or improved opioid drugs. At this juncture, it seems fitting to summarize the past twenty or so years of research on molecular imaging of the opioid system from the viewpoint of drug discovery and development. Opioid receptors were first imaged in human volunteers by positron emission tomography (PET) in 1984. Now, quantitative PET imaging of the major opioid receptor types (micro, delta , kappa) is possible in the brain and peripheral organs of healthy persons and patient populations. Radioligands are under development for single photon emission computed tomography (SPECT) of opioid receptors as well. These functional, nuclear imaging techniques can trace the fate of radiolabeled molecules directly, but non-invasively, and allow precise pharmacokinetic and pharmacodynamic measurements. Molecular imaging provides unique data that can aid in selecting the best drug candidates, determining optimal dosing regimens, clearing regulatory hurdles and lowering risks of failure. Using a historical perspective, this review touches on opioid receptors as drug targets, and focuses on the status and use of radiotracers for opioid receptor PET and SPECT. Selected studies are discussed to illustrate the power of molecular imaging for facilitating opioid drug discovery and development.     

Imaging techniques for assessing drug delivery in man

In vivo imaging technologies have a vital role to play in the pharmaceutical development process. Gamma scintigraphy, comprising two-dimensional ‘planar' imaging, is used widely to visualize and to quantify drug delivery, particularly by the oral and pulmonary routes. However, three-dimensional imaging modalities – single photon emission computed tomography (SPECT), positron emission tomography (PET) and magnetic resonance imaging (MRI) – may also have applications within this area. Single photon emission computed tomography and PET offer potential advantages over gamma scintigraphy in the assessment of regional lung deposition from aerosol inhalers, but these advantages are greatly outweighed by the practical problems associated with conducting SPECT and PET studies. It is concluded that, for the foreseeable future, gamma scintigraphy is the imaging modality of choice in assessing the delivery of new oral and pulmonary drug products.     

Positron emission tomographic imaging in drug discovery

Positron emission tomography (PET) is an extensively used nuclear functional imaging technique, especially for central nervous system (CNS) and oncological disorders. Currently, drug development is a lengthy and costly pursuit. Imaging with PET radiotracers could be an effective way to hasten drug discovery and advancement, because it facilitates the monitoring of key facets, such as receptor occupancy quantification, drug biodistribution, pharmacokinetic (PK) analyses, validation of target engagement, treatment monitoring, and measurement of neurotransmitter concentrations. These parameters demand careful analyses for the robust appraisal of newly formulated drugs during preclinical and clinical trials. In this review, we discuss the usage of PET imaging in radiopharmaceutical development; drug development approaches with PET imaging; and PET developments in oncological and cardiac drug discovery.     

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.     

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.     

ImmunoPET imaging of hematological malignancies: From preclinical promise to clinical reality

Immuno-positron emission tomography (immunoPET) imaging is a paradigm-shifting imaging technique for whole-body and all-lesion tumor detection, based on the combined specificity of tumor-targeting vectors [e.g., monoclonal antibodies (mAbs), nanobodies, and bispecific antibodies] and the sensitivity of PET imaging. By noninvasively, comprehensively, and serially revealing heterogeneous tumor antigen expression, immunoPET imaging is gradually improving the theranostic prospects for hematological malignancies. In this review, we summarize the available literature regarding immunoPET in imaging hematological malignancies. We also highlight the pros and cons of current conjugation strategies, and modular chemistry that can be leveraged to develop novel immunoPET probes for hematological malignancies. Lastly, we discuss the use of immunoPET imaging in guiding antibody drug development.     

Influence of particle size on regional lung deposition--what evidence is there?

The understanding of deposition of particles in the respiratory tract is of great value to risk assessment of inhalation toxicology and to improve efficiency in drug delivery of inhalation therapies. There are three main basic mechanisms of particle deposition based primarily on particle size: inertial impaction, sedimentation and diffusion. The regional deposition in the lungs can be evaluated in regards to the aerodynamic particle size, in which particle density plays a significant role. In this review paper, we first introduce the available imaging techniques to confirm regional deposition of particles in the human respiratory tract, such as planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET). These technologies have widely advanced and consequently benefited the understanding of deposition pattern, although there is a lack of lung dosimetry techniques to evaluate the deposition of nanoparticles. Subsequently, we present a comprehensive review summarizing the evidence available in the literature that confirms the deposition of smaller particles in the smaller airways as opposed to the larger airways.     

Regional pharmacokinetics of orally administered PET tracers

Positron emission tomography (PET) is currently the most useful imaging technique for noninvasive measurement of drug pharmacokinetics regionally in a variety of tissues. Over the past decade, PET measurements have provided many critical insights about the tissue distribution of several classes of drugs; neuroleptics, antimicrobials, antineoplastics, etc. PET measurements can be performed after any route of drug administration, intravenous, inhalation or oral, however, intravenously administered drugs have been the most extensively evaluated. Studies of orally administered drugs are clearly of great interest; however, formulation issues have precluded widespread applications in these areas. In this report, we discuss the unique problems associated with studying orally administered drugs and review the results of recent studies performed in our laboratory.