Drug development, radiolabelled drugs and PET

Positron emission tomography (PET) provides noninvasive in vivo quantitative pharmacokinetic and pharmacodynamic information on novel and established drugs. Because only very low amounts of the (potential) drug have to be administered, far below toxicity levels, human studies can be carried out even before the drug is entered in phase I studies. Such studies can provide cost-effective predictive toxicology data and information on the metabolism and mode of action of drugs. PET is also very useful in the study of the metabolic consequences of gene expression or gene defects. In the last decade, several models using genetically engineered small animals have been developed. The study of these animals with high-resolution small animal PET cameras provides new opportunities in drug development. Especially valuable is the contribution of PET in bridging the gap between molecular biology, basic pathology and the design of a new generation of drugs.     

Drug development,radiolabeled drugs and PET

Positron emission tomography (PET) provides noninvasive in vivo quantitative pharmacokinetic and pharmacodynamic information on novel and established drugs. Because only very low amounts of the (potential) drug have to be administered, far below toxicity levels, human studies can be carried out even before the drug is entered in phase I studies. Such studies can provide cost-effective predictive toxicology data and information on the metabolism and mode of action of drugs. PET is also very useful in the study of the metabolic consequences of gene expression or gene defects. In the last decade, several models using genetically engineered small animals have been developed. The study of these animals with high-resolution small animal PET cameras provides new opportunities in drug development. Especially valuable is the contribution of PET in bridging the gap between molecular biology, basic pathology and the design of a new generation of drugs.     

Ligand-receptor interactions as studied by PET: implications for drug development

Positron emission tomography (PET) is a quantitative imaging method that can be used to characterize binding properties of specific target molecules such as various receptors, transporter molecules and enzymes in vivo. Although already applied successfully, one of the greatest challenges for the technique is to understand better the in vivo complexities of ligand-receptor (target) interaction. The PET technique can be used efficiently in animal studies but, most importantly, also in human studies. PET imaging of patients and healthy volunteers can generate information on human pathophysiology at a molecular level currently unobtainable with other methods. Modern imaging techniques are increasingly applied to drug discovery and development. There are many ways of utilizing PET in pharmacodynamic studies, one interesting approach being the indirect exploration of synaptic neurotransmission with receptor ligands. The receptor occupancy-type studies with PET are rapidly becoming a state-of-the-art method for verifying the mechanism of action of a given drug in man and especially for facilitating the dose-finding procedures in early drug development. Thus far, PET has been mainly applied to pharmacodynamic studies in the central nervous system but will be used also in other areas of drug development such as cardiovascular diseases and oncology.     

Molecular Imaging in Drug Discovery and Development: Potential and Limitations of Nonnuclear Methods

Noninvasive conventional imaging methods are established technologies in modern drug discovery and development providing valuable morphological, physiological, and metabolic information to characterize disease phenotypes, to evaluate the efficacy of therapy and to identify and develop potential biomarkers for clinical drug evaluation. The development of target-specific or molecular imaging has added a new dimension: molecular events such as the target expression, the drug–target interaction, or the activation of signal transduction pathways can be studied in the intact organism with high spatial and temporal resolution. Molecular imaging is inherently a multimodality approach. In this article, we review the role of molecular imaging for drug discovery and development focusing on nonnuclear imaging methods, i.e., magnetic resonance imaging (MRI) and optical imaging techniques based on fluorescence and bioluminescence readouts. Examples discussed are direct visualization of target expression using target-specific ligands or reporter genes, pathway imaging, and cell-trafficking studies.     

Molecular PET and CT Imaging of Inflammation and Metabolism in Atherosclerosis

The molecular and biological processes that take place in atherosclerotic plaque play an important role in determining the pathologic progression of the plaque. Current imaging techniques primarily inform about plaque structure and thus fail to assess the functional aspects of atherosclerosis. Accordingly, imaging of plaque biology might provide important incremental information about the underlying disease process. An emerging body of work shows that molecular imaging with fluorodeoxyglucose—positron emission tomography (PET) can provide information about plaque biology. This review provides an overview of the development of vascular PET imaging, with an evaluation of current and potential future uses of this imaging modality.     

Overview of radiopharmaceuticals for diagnosis of central nervous disorders

There are two types of imaging instruments, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) that use radiopharmaceuticals for the diagnosis of brain disorders. Brain perfusion imaging agents, labeled either with 123I or 99mTc, are useful in detecting various cerebral vascular abnormalities, such as stroke and transient ischemia with SPECT. The management of other neurological disorders (i.e., in Alzheimer's, epilepsy, schizophrenia, and head trauma patients) may also be benefitted by these agents. The exact trapping mechanisms and their relationships with potential clinical applications still remain to be elucidated. Imaging studies using 18F fluorodeoxyglucose with PET is currently the most promising diagnostic tool for the evaluation of local glucose metabolism related to various disease states, such as Alzheimer's disease, brain tumor, and epilepsy. In the past few years significant progress has been made in the design and characterization of new CNS neuronal and postsynaptic receptor imaging agents for PET and SPECT. The new diagnostic agents are aimed at measurements of localization and changes of neuronal function. It is likely that these types of agents have potential for clinical application, especially in the diagnosis of psychiatric disorders that do not involve morphological changes.     

PET受体显像的研究应用进展

近年来,PET和PET/CT技术发展迅速,大量研究表明其在疾病的诊断、疗效监测和预后判断中具有重要临床价值。随着新型正电子放射性药物相继出现,尤其是正电子受体显像剂的开发研究应用,进一步推动和拓展了PET和PET/CT在临床的广泛应用,PET和PET/CT受体显像研究领域引人瞩目。     

New frontiers of MRI in Crohn’s disease: motility imaging, diffusion-weighted imaging, perfusion MRI, MR spectroscopy, molecular imaging, and hybrid imaging (PET/MRI)

This article reviews the latest diagnostic advances in the evaluation of the CD, including functional studies on intestinal motility and molecular characterization of the inflammatory process at the level of the involved bowel. Molecular changes related to inflammation of the intestinal wall may be evaluated by different MRI techniques, including diffusion-weighted imaging, perfusion weighted imaging, in vivo spectroscopy, molecular imaging, and fusion imaging (PET?CMRI).     

Weaving Single Photon Imaging into New Drug Development

The specific aim of this review is to assess the potential contribution of single photon emitting radiopharmaceutical technologies to new drug development. For each phase of therapeutic drug development, published literature was sought that shows single photon emitters can add value by quantifying pharmacokinetics, visualizing mechanisms of drug action, estimating therapeutic safety indices, or measuring dose-dependent pharmacodynamic effects. Not any published reports were found that describe using nuclear medicine techniques to help manage the progress of a new drug development program. As a consequence, most of the case in favor of weaving single photon imaging into the process had to be built on extrapolations from studies that showed feasibility post hoc. The strongest evidence of potential value was found for drug candidates that hope to influence diseases characterized by cell proliferation or cell death, particularly in the fields of oncology, cardiology, nephrology, and inflammation. Receptor occupancy studies were observed to occasionally offer unique advantages over analogous studies with positron emission tomography (PET). Enough hard data sets were found to justify the costs of using single photon imaging in a variety of new drug development paradigms.     

Positron emission tomography with 2-deoxy-2-[(18)F]fluoro-D-glucose for evaluating local and distant disease in patients with cervical cancer.

PURPOSE: To assess the accuracy of positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) for evaluating local and distant disease in patients with cervical cancer. METHODS: The PET imaging database maintained at our institution was used to identify patients who received FDG-PET scans for the clinical indication of cervical cancer for the past four years. Patients were followed for a minimum of six months following the PET study. Results of the FDG-PET studies were correlated with surgical pathology, biopsy results, and/or clinical follow up to assess the accuracy of FDG-PET in evaluating local and distant disease. RESULTS: A total of 61 FDG-PET studies performed in 41 patients were included in this retrospective study. Nine FDG-PET studies were performed for initial staging of cervical cancer, and 52 PET scans were performed in 35 different patients as restaging studies following therapy. For the initial staging, the local primary disease was identified in all nine FDG-PET studies, and PET distinguished the patients which had localized disease (four patients) from those with distant metastases on follow-up (five patients) with 100% accuracy. For restaging cervical cancer, FDG-PET had a sensitivity of 0.82 and specificity of 0.97 (accuracy 0.92) for evaluation of local recurrence. For evaluating distant disease in these patients, PET had a sensitivity of 1.00 and specificity of 0.90 (accuracy 0.94). In the evaluation of local disease, focal rectal activity caused false-positive results in two cases. Three false-positive studies for distant disease were caused by inflammatory adenopathy. CONCLUSION: FDG-PET is an accurate modality both for initial staging and restaging of patients with cervical cancer. PET is particularly sensitive for detecting distant metastases, allowing stratification of patients into those with locally confined disease and those with distant disease. These results were achieved by using a standardized PET imaging protocol without the use of bowel preparations, lasix administration, or Foley catheter drainage. Evaluation of local disease can be challenging due to adjacent rectal and bladder activity, and the use of hybrid PET/computed tomography (CT) scanners in the future may further improve evaluation of local disease.     

The clinical use of imaging techniques with exercise testing

The addition of nuclear imaging techniques to basic exercise electrocardiography (ECG) has provided significant diagnostic and prognostic information in the evaluation of patients with suspected coronary artery disease. During the last decade, new classes of isotopes (technetium-and rubidium-based perfusion agents) and refinements in single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have become better accepted. These new studies have added to the diagnostic armamentarium available to physicians, but at considerable costs with an estimated 4.8 million procedures performed this year. Nuclear imaging techniques can assess myocardial blood flow (perfusion imaging) or function (ventriculography). Another imaging modality, stress echocardiography, has also achieved widespread acceptance with clinical guidelines for its use published in 1997. This review addresses these imaging techniques in diagnostic evaluation of the patient with suspected coronary artery disease.     

The role of positron emission tomography in neuropharmacology in the living human brain and drug development

Neuroimaging is a powerful and innovative tool for studying the pathology of psychiatric and neurological diseases and, more recently, for studying the drugs used in their treatment. Technological advances in imaging have made it possible to noninvasively extract information from the human brain regarding a drug's mechanism and site of action. Until now, our understanding of human brain pharmacology has depended primarily on indirect assessments or models derived from animal studies. However, the advent of multiple techniques for human brain imaging allows researchers to focus directly on human pharmacology and brain function. In this review article, our PET studies on histaminergic neuron system were presented as an example. We have developed and used the PET techniques for 10 years in order to examine the functions of histaminergic neurons in the living human brain. This review outlines available PET techniques and examines how these various methods have already been applied to the drug development process and neuropharmacology in the living human brain.     

Animal Models of Neurodegenerative Disease: Insights from <Emphasis Type="Italic">In vivo</Emphasis> Imaging Studies

Animal models have been used extensively to understand the etiology and pathophysiology of human neurodegenerative diseases, and are an essential component in the development of therapeutic interventions for these disorders. In recent years, technical advances in imaging modalities such as positron emission tomography (PET) and magnetic resonance imaging (MRI) have allowed the use of these techniques for the evaluation of functional, neurochemical, and anatomical changes in the brains of animals. Combining animal models of neurodegenerative disorders with neuroimaging provides a powerful tool to follow the disease process, to examine compensatory mechanisms, and to investigate the effects of potential treatments preclinically to derive knowledge that will ultimately inform our clinical decisions. This article reviews the literature on the use of PET and MRI in animal models of Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease, and evaluates the strengths and limitations of brain imaging in animal models of neurodegenerative diseases.     

Imaging of gastrointestinal absorption and biodistribution of an orally administered probe using positron emission tomography in humans

The purpose of this study was to establish a method for imaging the process of gastrointestinal (GI) absorption and subsequent biodistribution in the human body after oral drug administration, using positron emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG). First, we developed a method to deliver the radiotracer safely into the stomach using soft gelatin capsules to avoid any significant exposure to the pharyngoesophageal region. Second, we performed pharmacokinetic (PK) analyses on time-radioactivity profiles in GI tissues and blood to calculate the gastric emptying and intestinal elimination rate constants and to estimate the fluid volume in the lumen of the small intestine from PET image analysis. This is the first study involving oral administration of a PET probe in humans, and the results demonstrate the high potential of PET technology to investigate the GI absorption and PK profiles of drugs in humans.     

Preclinical Characterization of the Phosphodiesterase 10A PET Tracer [<Superscript>11</Superscript>C]MK-8193

Purpose

A positron emission tomography (PET) tracer for the enzyme phosphodiesterase 10A (PDE10A) is desirable to guide the discovery and development of PDE10A inhibitors as potential therapeutics. The preclinical characterization of the PDE10A PET tracer [¹¹C]MK-8193 is described.

Procedures

In vitro binding studies with [³H]MK-8193 were conducted in rat, monkey, and human brain tissue. PET studies with [¹¹C]MK-8193 were conducted in rats and rhesus monkeys at baseline and following administration of a PDE10A inhibitor.

Results

[³H]MK-8193 is a high-affinity, selective PDE10A radioligand in rat, monkey, and human brain tissue. In vivo, [¹¹C]MK-8193 displays rapid kinetics, low test-retest variability, and a large specific signal that is displaced by a structurally diverse PDE10A inhibitor, enabling the determination of pharmacokinetic/enzyme occupancy relationships.

Conclusions

[¹¹C]MK-8193 is a useful PET tracer for the preclinical characterization of PDE10A therapeutic candidates in rat and monkey. Further evaluation of [¹¹C]MK-8193 in humans is warranted.

     

Neuroimaging of Alzheimer disease: current role and future potential

Alzheimer disease (AD), the most common cause of dementia in the elderly, is a progressive neurodegenerative disorder, associated with deterioration in cognition and behaviour. With the availability of newer drugs for symptoms treatments there is a general agreement to the need of an early diagnosis and an the development of new sensitive tools, to identify and/or monitor early cerebral changes, suggestive for AD. CT and MRI are recommended for routine evaluation, in order to exclude treatable causes of dementia and to exactly evaluate the degree of cerebral atrophy and the presence of parenchymal signal abnormalities. Functional imaging, including PET, SPECT and functional MR techniques, are able to investigate physiological cerebral function, such as blood perfusion, metabolism, activation, molecular composition and water diffusibility, and have the potential to detect subtle pathological changes earlier during course of disease. MRI can provide both an accurate morphological assessment and a functional evaluation. Further investigations are needed to precisely define which will be the role of the different MR techniques. Most likely an exhaustive evaluation of AD will include information obtained by conventional and functional imaging, combined with clinical, laboratory and genetic findings.     

The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies

Histamine neurons are exclusively located in the posterior hypothalamus, and project their fibers to almost all regions of the human brain. Although a significant amount of research has been done to clarify the functions of the histaminergic neuron system in animals, a few studies have been reported on the roles of this system in the human brain. In past studies, we have been able to clarify some of the functions of histamine neurons using different methods, such as histamine-related gene knockout mice or human positron emission tomography (PET). The histaminergic neuron system is known to modulate wakefulness, the sleep-wake cycle, appetite control, learning, memory and emotion. Accordingly we have proposed that histamine neurons have a dual effect on the CNS, with both stimulatory and suppressive actions. As a stimulator, neuronal histamine is one of the most important systems that stimulate and maintain wakefulness. Brain histamine also functions as a suppressor in bioprotection against various noxious and unfavorable stimuli of convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress susceptibility. This review summarizes our works on the functions of histamine neurons using human PET studies, including the development of radiolabeled tracers for histamine H1 receptors (H1R: (11)C-doxepin and (11)C-pyrilamine), PET measurements of H1R in depression, schizophrenia, and Alzheimer's disease (AD), and studies on the sedative effects of antihistamines using H(2)(15)O and H1R occupancy in the human brain. These molecular and functional PET studies in humans are useful for drug development in this millennium.     

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

Adenosine A_2A receptors (A_2ARs) 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. A_2AR 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 A_2AR signaling in adipose tissue is also a potential strategy to combat obesity. Several radioligands for positron emission tomography (PET) imaging of A_2ARs have been developed in recent years. This review article presents a critical overview of the potential therapeutic applications of A_2AR ligands, the use of A_2AR imaging in drug development, and opportunities and limitations of PET imaging in future research.     

Positron emission tomography studies of brain receptors

Probing the regional distribution and affinity of receptors in the brain, in vivo, in human and non human primates has become possible with the use of selective ligands labelled with positron emitting radionuclides and positron emission tomography (PET). After describing the techniques used in positron emission tomography to characterize a ligand receptor binding and discussing the choice of the label and the limitations and complexities of the in vivo approach, the results obtained in the PET studies of various neurotransmission systems: dopaminergic, opiate, benzodiazepine, serotonin and cholinergic systems are reviewed.