A rational regulatory approach for positron emission tomography imaging probes: from "first in man" to NDA approval and reimbursement.

We propose a new regulatory approach for positron emission tomography (PET) molecular imaging probes, essential tools in today's medicine. Even though the focus of this paper is on positron-emitting labeled probes, it is also justified to extend this proposed regulatory approach to other diagnostic nuclear medicine radiopharmaceuticals. Key aspects of this proposal include: (1) PET molecular imaging probes would be placed in a "no significant risk" category, similar to that category for devices in current Food and Drug Administration (FDA) regulations, based on overwhelming scientific evidence that demonstrates their faultless safety profile; (2) the FDA-sanctioned Radioactive Drug Research Committee (RDRC) will oversee all diagnostic research with these probes. The newly defined RDRC should approve "first in man" use; supervise a broader spectrum of diagnostic research protocols, including those looking to demonstrate initial efficacy, as well as multicenter clinical trials and the use of molecular imaging probes as a screening tool in drug discovery. The current investigational new drug (IND) mechanism is thus eliminated for these diagnostic probes; (3) when a molecular imaging probe has demonstrated diagnostic efficacy, FDA approval (i.e., NDA) will be sought. The review will be done by a newly constituted Radioactive Drug Advisory Committee (RDAC) composed of experts chosen by the professional societies, who would provide a binding assessment of the adequacy of the safety and efficacy data. When the RDAC recommends its diagnostic use on scientific and medical grounds, the molecular imaging probe becomes FDA approved. After a molecular imaging probe is approved for a diagnostic indication, the existing mechanism to seek reimbursement will be utilized; and (4) the FDA would retain its direct oversight function for traditional manufacturers engaged in commercial distribution of the approved diagnostic molecular imaging probes (i.e., under NDA) to monitor compliance with existing US Pharmacopeia (USP) requirements. With abbreviated and more appropriate regulations, new PET molecular imaging probes for diagnostic use would be then rapidly incorporated into the mainstream diagnostic medicine. Equally importantly, this approach would facilitate the use of molecular imaging in drug discovery and development, which would substantially reduce the costs and time required to bring new therapeutic drugs to market.     

Tracing transgene expression in cancer gene therapy: a requirement for rational progress in the field.

This review summarizes the status of gene therapy in medicine and the role of molecular imaging in its development. In gene therapy, genetic material is introduced into cells in order to generate a specific biological effect. Natural (viruses) or artificial molecular constructs, named gene therapy vectors, are used to achieve efficient cell transduction. This new form of therapy can be used for treating a broad variety of conditions including hereditary diseases, infections, degenerative disorders and cancer. Monitoring transgene expression using noninvasive imaging techniques is a necessary complement for the development of clinical gene therapy. Recent developments in magnetic resonance imaging afford the possibility of detecting gene transfer in vivo, but the most promising results have been obtained with positron emission tomography (PET). PET allows imaging gene therapy products by administration of a labeled substrate when the transgene codes for an enzyme or by administration of a labeled ligand when the transgene codes for a receptor. In the latter strategy, a membrane molecule (somatostatin or dopamine receptors) is used to detect the selective trapping of its radiolabeled ligand in the transduced cells. One of the approaches for the genetic treatment of cancer consists in transferring the "suicide genes" into tumor cells, the most common being the thymidine kinase (tk) of herpes viruses. Different nucleoside analogs can be labeled for its use as PET reporter probes in order to visualize tk expression. The results of pre-clinical studies are extremely encouraging. Reliable methods for the in vivo tracing of transgene expression in humans have to be developed in order for the field of gene therapy to mature. PET has emerged as a powerful tool to assist in achieving this goal.     

Small animal positron emission tomography imaging and in vivo studies of atherosclerosis

Atherosclerosis is a growing health challenge globally, and despite our knowledge of the disease has increased over the last couple of decades, many unanswered questions remain. As molecular imaging can be used to visualize, characterize and measure biological processes at the molecular and cellular levels in living systems, this technology represents an opportunity to investigate some of these questions in vivo. In addition, molecular imaging may be translated into clinical use and eventually pave the way for more personalized treatment regimes in patients. Here, we review the current knowledge obtained from in vivo positron emission tomography studies of atherosclerosis performed in small animals.     

Positron Emission Tomography Imaging of Small Animals in Anticancer Drug Development

Positron emission tomography (PET) imaging of small animals enables researchers to bridge the gap between in vitro science and in vivo human studies. The imaging paradigm can be established and refined in animals before implementation in humans and image data related to ex vivo assays of biological activity. Small animal PET (saPET) imaging enables assessment of baseline focal pathophysiology, pharmacokinetics, biological target modulation and the efficacy of novel drugs. The potential and challenge of this technology as applied to anticancer drug development is discussed here.     

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.     

In vivo molecular imaging biomarkers: clinical pharmacology's new "PET"?

Medicine, including the pharmaceutical and biotechnology industries as well as many clinical practitioners, has recognized the importance of using molecular imaging biomarkers, including those labeled in such a way as to be imaged by positron emission tomography (PET), as tools for predicting outcomes in drug development and creating opportunities for "personalized" medicine, for diagnosing early-stage disease, and for the follow-up of the effectiveness of treatment.(1) However, only one important and widely used PET biomarker is currently approved by the Food and Drug Administration (FDA). If the technology is so important, we can ask why there is such a limitation to the availability of these biomarkers.     

PET in cardiology: current status and clinical expectations

Summary. The development of positron emission tomography (PET) in the clinical environment along with the synthesis of biologically active molecules and tracer kinetic principles has provided a diagnostic tool for in vivo tissue characterization in humans. Moreover, based on the growing knowledge of cellular function on the molecular level of diseases PET biological imaging has stimulated the synthesis of numerous metabolic compounds labelled with the four primary positron-emitting radioisotopes C-ll, F-18, N-13 and 0–15. While the concept of biological imaging has gained attraction for probing both the central nervous system and neoplastic tissues, current diagnostic benefit from PET is probably best defined in cardiovascular medicine.     

PET and the role of in vivo molecular imaging in personalized medicine

In order for personalized medicine to become a clinical reality a number of hurdles, both technological and regulatory in nature, need to be addressed. Our ability to image biological and pathological processes at a molecular level using positron emission tomography (PET) imaging offers an unparalleled opportunity to radically reform the manner in which a disease is diagnosed and managed. The degree to which current innovations in PET science will translate into clinical practice, thereby impacting upon personalized medicine, is discussed.     

Positron emission tomography and gene therapy: basic concepts and experimental approaches for in vivo gene expression imaging.

More than two decades of intense research have allowed gene therapy to move from the laboratory to the clinical setting, where its use for the treatment of human pathologies has been considerably increased in the last years. However, many crucial questions remain to be solved in this challenging field. In vivo imaging with positron emission tomography (PET) by combination of the appropriate PET reporter gene and PET reporter probe could provide invaluable qualitative and quantitative information to answer multiple unsolved questions about gene therapy. PET imaging could be used to define parameters not available by other techniques that are of substantial interest not only for the proper understanding of the gene therapy process, but also for its future development and clinical application in humans. This review focuses on the molecular biology basis of gene therapy and molecular imaging, describing the fundamentals of in vivo gene expression imaging by PET, and the application of PET to gene therapy, as a technology that can be used in many different ways. It could be applied to avoid invasive procedures for gene therapy monitoring; accurately diagnose the pathology for better planning of the most adequate therapeutic approach; as treatment evaluation to image the functional effects of gene therapy at the biochemical level; as a quantitative noninvasive way to monitor the location, magnitude and persistence of gene expression over time; and would also help to a better understanding of vector biology and pharmacology devoted to the development of safer and more efficient vectors.     

Molecular imaging of psychiatric disorders

Positron emission tomography (PET) techniques have made it possible to measure changes in target molecular in living human brain. PET can be used to investigate various brain functions such as receptors, transporters, enzymes and various biochemical pathways; therefore, it could be a powerful tool for molecular imaging of psychiatric disorders. Since dopamine is an important molecule for pathophysiology of schizophrenia, we reviewed in vivo imaging studies focusing on dopaminergic transmission in schizophrenia. Dopamine D2 receptor occupancy by antipsychotics and it' s time-course have been measured using PET. This approach can provide in vivo pharmacological evidences of antipsychotics and establish the rational therapeutic strategy. PET is a powerful tool not only in the field of brain research but also drug discovery.     

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.     

Positron emission tomography as a tool for translational research in oncology.

Growing knowledge of the molecular mechanisms of oncological disease plays a key role in the improvement of prevention, diagnosis and treatment of malignant tumors. In this review, positron emission tomography (PET) is described as a mediator between molecular oncological research and clinical management of tumor patients. The most promising applications of PET in the near future include tumor imaging with newly developed tracers for diagnosis, staging and grading purposes, therapy monitoring with proliferation and apoptosis markers and definition of the tumor environment (e.g. hypoxia, neoangiogenesis) prior to therapy. Many of these applications will greatly benefit from the use of integrated PET/CT due to its precise spatial and morphological assignment of functional information. In conclusion, PET is both capable and necessary for the transference of new biological knowledge to clinical practice. Thus, PET constitutes a strong basis for an advanced and individually tailored approach to tumor patients.     

Transport across the blood-brain barrier: stereoselectivity and PET-tracers.

This article reviews positron emission tomography (PET) studies of labeled enantiomers of different PET-tracers from the early 1980s. Comparative studies on stereoselective behavior of the transport of tracers across the blood-brain barrier (BBB) are discussed. Tracers are transported through the BBB into the brain, via diffusion or via several transport systems. These transport systems are able to transport endogenous and exogenous compounds from the blood into the brain, and visa versa. A clear difference exists in BBB transport of the enantiomers of several tracers. In addition, in most cases, binding of these labeled enantiomers to receptors/transporters is stereoselective. Finally, use of the biological inactive labeled enantiomer for the measurement of nonspecific binding is discussed. Given the differences in transport and binding, it is concluded that quantitative PET studies can only be performed using pure enantiomers.     

Cardiac Metabolic Implications of Fat Depot Imaging

Purpose of Review

This article reviews recent developments in the application of positron emission tomography (PET) for personalized cardiac imaging.

Recent Findings

PET imaging has improved our understanding of various cardiovascular pathologies by probing the molecular pathways associated with specific cardiovascular diseases. The use of PET can improve disease detection and influence management strategies.

Summary

PET has improved our understanding of the pathophysiology of atherosclerosis by imaging several key features including calcification, inflammation, apoptosis, and hypoxia. Molecular imaging of myocardial inflammation and cardiac sympathetic innervation is well established and several new promising PET radiotracers have been developed. Roles for the molecular imaging of aortic valve disease and mitochondrial function are also emerging.

     

体内肿瘤凋亡显像中PET探针的研究进展

细胞凋亡是生命的一种基本生理机制,对恶性肿瘤的发生和发展有重要意义。近年来,对细胞凋亡机制的研究已有重大进展。检测体内肿瘤细胞的凋亡状态及凋亡水平,对预测肿瘤生物学行为、指导个体化治疗具有重要意义。PET在凋亡显像研究中发挥着重要作用,新型分子探针的研制开发是核医学界研究的热点。     

Assessment of S Values in Stylized and Voxel-Based Rat Models for Positron-Emitting Radionuclides

Purpose

Positron emission tomography (PET) is a powerful tool in small animal research, enabling noninvasive quantitative imaging of biochemical processes in living subjects. However, the dosimetric characteristics of small animal PET imaging are usually overlooked, although the radiation dose may be significant. The variations of anatomical characteristics between the various computational models may result in differences in the dosimetric outcome.

Methods

We used five different anatomical rat models (two stylized and three voxel based) to compare calculated absorbed fractions and S values for eight positron-emitting radionuclides (C-11, N-13, O-15, F-18, Cu-64, Ga-68, Y-86, and I-124) commonly used to label various probes for small animal PET imaging. The MCNPX radiation transport code was used for radiation dose calculations.

Results

For most source/target organ pairs, O-15 and Ga-68 produce the highest self-absorbed S values because of the high-energy and high-frequency of positron emissions, while Y-86 produces the highest cross-absorbed S values because of the high energy and high frequency of γ-rays emission. Anatomical models produced from different rat strains or modeling techniques exhibit different organ masses, volumes, and thus give rise to different S values and absorbed dose. The variations of absorbed fractions between models of the same type are less than those between models with different types. The calculated S values depend strongly on organ mass, and as such, different models produce similar S values for organs of comparable masses. In most source organs presenting with high cumulated activity, the absorbed dose is less affected by model difference compared with other organs.

Conclusions

The produced S values for common positron-emitting radionuclides can be exploited in the assessment of radiation dose to rats from different radiotracers used in small animal PET experiments. This work contributes to a better understanding of the influence of different computational models on small animal dosimetry.     

Modification of Aminosilanized Superparamagnetic Nanoparticles: Feasibility of Multimodal Detection Using 3T MRI, Small Animal PET, and Fluorescence Imaging

Purpose

The aim of our study was to modify an aminosilane-coated superparamagnetic nanoparticle for cell labeling and subsequent multimodal imaging using magnetic resonance imaging (MRI), positron emission tomography (PET), and fluorescent imaging in vivo.

Procedures

We covalently bound the transfection agent HIV-1 tat, the fluorescent dye fluorescein isothiocyanate, and the positron-emitting radionuclide gallium-68 to the particle and injected them intravenously into Wistar rats, followed by animal PET and MRI at 3.0 T. As a proof of principle hepatogenic HuH7 cells were labeled with the particles and observed for cell toxicity as well as detectability by MRI and biodistribution in vivo.

Results

PET imaging and MRI revealed increasing hepatic and splenic accumulation of the particles over 24 h. Adjacent in vitro studies in hepatogenic HuH7 cells showed a rapid intracellular accumulation of the particles with high labeling efficiency and without any signs of toxicity. In vivo dissemination of the labeled cells could be followed by dynamic biodistribution studies.

Conclusions

We conclude that our modified superparamagnetic nanoparticles are stable under in vitro and in vivo conditions and are therefore applicable for efficient cell labeling and subsequent multimodal molecular imaging. Moreover, their multiple free amino groups suggest the possibility for further modifications and might provide interesting opportunities for various research fields.