Radionuclide imaging studies in the assessment of nasal drug delivery in humans

An understanding of the deposition and clearance of nasal drug formulations from the human nasal cavity is important in order to optimally exploit the nasal route for delivery of drugs intended for local or systemic applications. Three radionuclide imaging methods may be used to assess nasal drug delivery: (i) gamma scintigraphy; (ii) single photon emission computed tomography (SPECT); and (iii) positron emission tomography (PET). Gamma scintigraphy is used to image the nasal cavity in two dimensions, while SPECT and PET are 3-dimensional imaging methods. By quantifying the deposition and clearance of drug formulations, radionuclide imaging studies allow a comparison to be made between the performance of new nasal drug delivery systems and those already marketed. Imaging data have been used to demonstrate the bioadhesive properties of novel formulations in the nasal cavity and to show that little or no drug usually penetrates directly to the lungs when delivered intranasally. These data may have an important regulatory role by clarifying whether small in vitro differences between products are likely to be clinically significant. Gamma scintigraphy is likely to remain the most widely used radionuclide imaging method, at least for the time being, although a larger future role is likely for SPECT and PET.     

Radionuclide imaging technologies and their use in evaluating asthma drug deposition in the lungs

Whole lung and regional lung deposition of inhaled asthma drugs in the lungs can be quantified using either two-dimensional or three-dimensional radionuclide imaging methods. The two-dimensional method of gamma scintigraphy has been the most widely used, and is currently considered the industry standard, but the three-dimensional methods (SPECT, single photon emission computed tomography; and PET, positron emission tomography) give superior regional lung deposition data and will undoubtedly be used more frequently in future. Recent developments in radionuclide imaging are described, including an improved algorithm for assessing regional lung deposition in gamma scintigraphy, and a patent-protected radiolabelling method (TechneCoat), applicable to both gamma scintigraphy and SPECT. Radionuclide imaging data on new inhaled asthma products provide a milestone assessment, and the data form a bridge between in vitro testing and a full clinical trials program, allowing the latter to be entered with increased confidence.     

Challenges in assessing regional distribution of inhaled drug in the human lungs

INTRODUCTION: Both the total amount of drug deposited in the lungs (whole lung deposition) and the amount deposited in different lung regions (regional lung deposition) are potentially important factors that determine the safety and efficacy of inhaled drugs. Radionuclide imaging is well established for quantifying the whole lung deposition of inhaled drugs, but the assessment of regional lung deposition is less straightforward, because of the complex nature of the lung anatomy. AREAS COVERED: This review describes the challenges and problems associated with quantifying regional lung deposition by the two-dimensional (2D) radionuclide imaging method of gamma scintigraphy, and by the three-dimensional (3D) radionuclide imaging methods of single-photon-emission computed tomography (SPECT) and positron-emission tomography (PET). The advantages and disadvantages of each method for assessing regional lung deposition are discussed. EXPERT OPINION: Owing to its 2D nature, gamma scintigraphy provides limited information about regional lung deposition. SPECT provides regional lung deposition data in three dimensions, but usually involves a (99m)Tc radiolabel. PET enables the regional lung deposition of radiolabeled drug molecules to be quantified in three dimensions, but poses the greatest logistical and technical difficulties. Despite their more challenging nature, 3D imaging methods should be considered as an alternative to gamma scintigraphy whenever the determination of regional lung deposition of pharmaceutical aerosols is a major study objective.     

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.     

吸入制剂肺部沉积量测定的方法学研究进展

目的:介绍吸入制剂肺部沉积量的不同测定方法,为相关研究提供参考和思路。方法:采用文献检索的方式,搜索Pubmed、中国知网和万方数据库的相关文献,对其进行整理和分析,并将不同测定方法按其特点分类介绍。结果:吸入剂的肺部沉积量可通过影像学和非影像学方法来测定。影像学方法包括二维γ显像法、单光子发射计算机断层扫描(SPECT)、正电子发射断层扫描(PET)等;非影像学方法包括活性炭阻断法及尿排泄法。非影像学方法可使患者免受电离辐射的影响,而影像学方法可提供更多的局部沉积量信息。结论:不同测定方法均有其优势与局限性。目前国外监管部门较为认可的方法为γ显像法和非影像学方法,但部分非影像学方法在我国并未得到广泛应用,相信其在以后的应用会有所增加。     

Challenges in assessing regional distribution of inhaled drug in the human lungs

Introduction: Both the total amount of drug deposited in the lungs (whole lung deposition) and the amount deposited in different lung regions (regional lung deposition) are potentially important factors that determine the safety and efficacy of inhaled drugs. Radionuclide imaging is well established for quantifying the whole lung deposition of inhaled drugs, but the assessment of regional lung deposition is less straightforward, because of the complex nature of the lung anatomy.

Areas covered: This review describes the challenges and problems associated with quantifying regional lung deposition by the two-dimensional (2D) radionuclide imaging method of gamma scintigraphy, and by the three-dimensional (3D) radionuclide imaging methods of single-photon-emission computed tomography (SPECT) and positron-emission tomography (PET). The advantages and disadvantages of each method for assessing regional lung deposition are discussed.

Expert opinion: Owing to its 2D nature, gamma scintigraphy provides limited information about regional lung deposition. SPECT provides regional lung deposition data in three dimensions, but usually involves a ^99mTc radiolabel. PET enables the regional lung deposition of radiolabeled drug molecules to be quantified in three dimensions, but poses the greatest logistical and technical difficulties. Despite their more challenging nature, 3D imaging methods should be considered as an alternative to gamma scintigraphy whenever the determination of regional lung deposition of pharmaceutical aerosols is a major study objective.     

Imaging of cellular therapies

Cellular therapy promises to revolutionize medicine, by restoring tissue and organ function, and combating key disorders including cancer. As with all major developments, new tools must be introduced to allow optimization. For cell therapy, the key tool is in vivo imaging for real time assessment of parameters such as cell localization, numbers and viability. Such data is critical to modulate and tailor the therapy for each patient. In this review, we discuss recent work in the field of imaging cell therapies in the clinic, including preclinical work where clinical examples are not yet available. Clinical trials in which transferred cells were imaged using magnetic resonance imaging (MRI), nuclear scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET) are evaluated from an imaging perspective. Preclinical cell tracking studies that focus on fluorescence and bioluminescence imaging are excluded, as these modalities are generally not applicable to clinical cell tracking. In this review, we assess the advantages and drawbacks of the various imaging techniques available, focusing on immune cells, particularly dendritic cells. Both strategies of prelabeling cells before transplant and the use of an injectable label to target cells in situ are covered. Finally, we discuss future developments, including the emergence of multimodal imaging technology for cell tracking from the preclinical to the clinical realm.     

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.     

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.     

Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer

The recent developments of nuclear medicine in oncology have involved numerous investigations of novel specific tumor-targeting radiopharmaceuticals as a major area of interest for both cancer imaging and therapy. The current progress in pharmaceutical nanotechnology field has been exploited in the design of tumor-targeting nanoscale and microscale carriers being able to deliver radionuclides in a selective manner to improve the outcome of cancer diagnosis and treatment. These carriers include chiefly, among others, liposomes, microparticles, nanoparticles, micelles, dendrimers and hydrogels. Furthermore, combining the more recent nuclear imaging multimodalities which provide high sensitivity and anatomical resolution such as PET/CT (positron emission tomography/computed tomography) and SPECT/CT (combined single photon emission computed tomography/computed tomography system) with the use of these specific tumor-targeting carriers constitutes a promising rally which will, hopefully in the near future, allow for earlier tumor detection, better treatment planning and more powerful therapy. In this review, we highlight the use, limitations, advantages and possible improvements of different nano- and microcarriers as potential vehicles for radionuclides delivery in cancer nuclear imaging and radiotherapy.     

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.     

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.     

In-vivo Monitoring of Dosage Forms*

The use of imaging techniques including gamma scintigraphy to follow the behaviour of drug formulations has revolutionized our knowledge of absorption and distribution in drug delivery. The development of gamma camera techniques as physiological tools to explore organ function became routine by the mid-seventies. Several research groups started to explore the applications of technique in drug delivery. Within 5 years, the utility of the technique became obvious and scintigraphy is now widely accepted as an important investigation tool in formulation research. Gamma scintigraphy is especially useful in exploring sources of inter-subject variation, especially in examining food effects in pharmacokinetic estimations and establishing windows of absorption for oral delivery. As a tool to examine drug delivery to the lung and to the eye, scintigraphy is the method of choice. Magnetic Resonance Imaging (MRI) became more generally employed in medicine two decades after the gamma camera. The superior soft-tissue contrast and resolution compared to computed X-ray tomography rapidly established MRI in clinical investigation. Recent applications in oral drug research has allowed the pharmaceutical scientist to explore new facets of delivery and ultimately combine MRI and scintigraphy in human clinical trials.     

Lanthanide bearing microparticulate systems for multi-modality imaging and targeted therapy of cancer

The rapid developments of high-resolution imaging techniques are offering unique possibilities for the guidance and follow up of recently developed sophisticated anticancer therapies. Advanced biodegradable drug delivery systems, e.g. based on liposomes and polymeric nanoparticles or microparticles, are very effective tools to carry these anticancer agents to their site of action. Elements from the group of lanthanides have very interesting physical characteristics for imaging applications and are the ideal candidates to be co-loaded either in their non-radioactive or radioactive form into these advanced drug delivery systems because of the following reasons: Firstly, they can be used both as magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents and for single photon emission computed tomography (SPECT). Secondly, they can be used for radionuclide therapies which, importantly, can be monitored with SPECT, CT, and MRI. Thirdly, they have a relatively low toxicity, especially when they are complexed to ligands. This review gives a survey of the currently developed lanthanide-loaded microparticulate systems that are under investigation for cancer imaging and/or cancer therapy.     

Imaging the airways in 2006.

Imaging has traditionally been separated into two distinct disciplines: functional imaging and structural imaging. Functional imaging encompasses applications such as nuclear medicine (single photon emission computed tomography [SPECT] and positron emission tomography [PET]), autoradiography, magnetic resonance spectroscopy (MRS) and magneto-encephalography (MEG), while structural, or anatomical, imaging includes planar radiography, x-ray computed tomography (CT), and magnetic resonance imaging (MRI). However, today, the distinctions between these are blurring due to advances in software fusion and the development of multi-modality (SPECT/CT, PET/CT) scanners. New techniques such as MRI using hyperpolarized gases (3H and 129Xe) and xenon K-edge synchrotron x-ray subtraction imaging are also being developed to provide the researcher with a variety of ways to probe the airways, and the distribution of pharmaceuticals and subsequent uptake and bio-distribution. This paper reviews advances in imaging to present a contemporary view of the tools available.     

Development of radioligands for in vivo imaging of GABA(A)-benzodiazepine receptors

Changes in the biochemical integrity and function of the GABA(A)-benzodiazepine receptor (BZR) complex have been implicated in various neurological and psychiatric disorders. The development of specific radioligands for the GABA(A)-BZR have not only contributed to the elucidation of the receptor's biochemical functions, but also provided a means by which these changes are correlated to disease states when studied with the functional imaging modalities of positron emission tomography (PET) and single photon emission computed tomography (SPECT).     

Part II: targeted particles for imaging of anticancer immune responses

The interaction of dendritic cells (DCs) and T cells has been the cornerstone of approaches to cancer immunotherapy. Antitumoral immune responses can be elicited by delivering cancer antigens to DCs. As antigen presenting cells, these DCs activate cancer antigen specific T cells. Whereas the first part of the review discusses methods for delivery of cancer vaccines to DCs, in this part the focus is on the potential role of nanoscopic devices for molecular imaging of these immune responses. Nanoscopic devices could potentially deliver tracking molecules to DCs, enabling monitoring of DCs and/or T cell activation and tumoricidal activity during immunotherapy, using non-invasive imaging modalities such as nuclear imaging (single photon emission computed tomography (SPECT), positron emission tomography (PET)), magnetic resonance imaging (MRI) and optical imaging.     

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.     

Deposition, imaging, and clearance: what remains to be done?

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.     

PET studies of brain monoamine transporters

Monoamine transporters are proteins mainly located on nerve terminals of dopaminergic, noradrenergic and serotonergic neurons. They are members of a larger sodium dependent transporter family and represent a major mechanism terminating the action of released neurotransmitter in the synaptic cleft. In addition to being important target molecules for many antidepressive drugs and substances of abuse, transporter proteins are good markers for the integrity of monoaminergic innervation. Therefore, there is a growing interest for in vivo imaging studies using positron emission tomography (PET) or single photon emission computed tomography (SPECT) and ligands selective for monoamine transporters. In this review, the use of monoamine transporter ligands (or tracers) for imaging studies of cocaine dependence, neurodegenerative diseases and mechanism of antidepressant drug action is discussed, with special focus on the use of PET for evaluating possible new pharmacological innovations.