PET and SPET molecular imaging: focus on serotonin system

Emission tomography techniques and, in particular, positron emission tomography (PET) enable the in vivo study of several physiological and neurochemical variables in human subjects using methods originally developed for quantitative autoradiography. In particular, PET allows one to evaluate in human subjects: (a) the effect of specific neurochemical challenges on regional brain function at rest or under activation; (b) the activity of neurotransmitters and the regional expression of specific molecular targets during pathology including their modulation by drug treatment; (c) the kinetics of drug disposition and activity directly in the target organ. This is of primary interest in the field of biological psychiatry and in psychoactive drugs development, where it is particularly difficult to reproduce human diseases using animal models in view of the peculiarity of this field and the large heterogeneity of each psychiatric illness also inside the same clinical definition. The aim of this paper is to review the principal strategies and the main results of the use of PET or single photon emission tomography (SPET) molecular imaging for the in vivo study of serotonin receptors and the main results obtained from their application in the study of major depression.     

Imaging addiction with PET: is insight in sight?

Neurochemical imaging studies can identify molecular targets of abused drugs and link them to the underlying pathology associated with behaviors such as drug dependence, addiction and withdrawal. positron emission tomography (PET) is opening new avenues for the investigation of the neurochemical disturbances underlying drug abuse and addiction and the in vivo mechanisms by which medications might ameliorate these conditions. PET can identify vulnerable human populations, treatment strategies and monitor treatment efficacy. Thus, with this tool and the knowledge it provides, the potential for developing novel drugs and treatment strategies for drug addiction is now close at hand.     

PET in psychopharmacology.

Emission tomography techniques and, in particular, positron emission tomography (PET) enable the in vivo study of several physiological and neurochemical variables in human subjects using methods originally developed for quantitative autoradiography. In particular, PET allows one to evaluate in human subjects: (a) the effect of specific neurochemical challenges on regional brain function at rest or under activation; (b) the activity of neurotransmitters and the regional expression of specific molecular targets during pathology including their modulation by drug treatment; (c) the kinetics of drug disposition and activity directly in the target organ. This is of primary interest in the field of biological psychiatry and in psychoactive drugs development, where it is particularly difficult to reproduce human diseases using animal models in view of the peculiarity of this field and the large heterogeneity of each psychiatric illness also inside the same clinical definition. The aim of this paper is to review the principal strategies and the main results of the use of PET in psychopharmacology.     

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.     

Contributions of neuroimaging to understanding sex differences in cocaine abuse

A consistent observation in drug abuse research is that males and females show differences in their response to drugs of abuse. In order to understand the neurobiology underlying cocaine abuse and effective treatments, it is important to consider the role of sex differences. Sex hormones have been investigated in both behavioral and molecular studies, but further evidence addressing drug abuse and dependence in both sexes would expand our knowledge of sex differences in response to drugs of abuse. Neuroimaging is a powerful tool that can offer insight into the biological bases of these differences and meet the challenges of directly examining drug-induced changes in brain function. As such, neuroimaging has drawn much interest in recent years. Specifically, positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) technology have emerged as effective noninvasive approaches for human and animal models. Studies have revealed sex-specific changes in patterns of brain activity in response to acute cocaine injection and after prolonged cocaine use. SPECT and PET studies have demonstrated changes in the dopamine transporter but are less clear on other components of the dopaminergic system. This review highlights contributions of neuroimaging toward understanding the role of sex differences in the drug abuse field, specifically regarding cocaine, and identifies relevant questions that neuroimaging can effectively address.     

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.     

Imaging of the brain cannabinoid system

This review covers two major strategies for imaging of the brain cannabinoid system: autoradiography and in vivo neuroimaging. Cannabinoid receptors can be imaged directly with autoradiography in brain slices using radiolabeled cannabinoid receptor ligands. In addition, the effects of pharmacologic doses of unlabeled cannabinoid drugs can be autoradiographically imaged using indicators of blood flow or indicators of metabolism such as glucose analogs. Although cannabinoid imaging is a relatively new topic of research compared to imaging of other drugs of abuse, autoradiographic strategies have produced high-quality information about the distribution of brain cannabinoid receptors and the effects of cannabinoid drugs on brain metabolism. In vivo neuroimaging, in contrast to autoradiography, utilizes noninvasive techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) to image both the binding and the effects of drugs within living brain. These techniques are well developed; however, in vivo imaging of cannabinoid systems is in a very preliminary state. Early results have been promising yet hard to generalize. Definitive answers to some of the most important questions about cannabinoid drugs and their effects await development of suitable in vivo neuroimaging ligands for cannabinoid systems.     

Radioligands for the study of the 5-HT transporter in vivo

Loss of 5-HT transporter (SERT) sites has been implicated in various neurodegenerative diseases and users of some amphetamine derivatives such as MDMA. Therefore, the development of suitable radioligands for neuroimaging of the SERT in the human brain is important. A large number of drugs have been labeled with 11C, 18F or (123)I over the last ten years in order to achieve such radioligands. Despite these attempts most of the compounds were found unsuitable because of low target-to-nontarget ratios. Some cocaine-derived radioligands allow SERT imaging of the human brain using positron emission tomography (PET) although they have a limited selectivity. Among the various specific 5-HT uptake inhibitors only [(123)I]iodo-nitroquipazine for single photon emission computed tomography (SPECT) and [11C](+)McN5652 for PET appear to meet the criteria of a useful radioligand. There is still a need for the development of new radioligands for SERT imaging. Advances in tracer synthetic methodologies may bring further progress in this field.     

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.     

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.     

Imaging neurochemical endophenotypes: promises and pitfalls

A large number of polymorphisms in genes coding for neurotransmitter receptors and transporters have been associated with neuropsychiatric conditions, although few of these associations have been consistently replicated. These proteins are critical targets of psychoactive drugs and the clarification of the functional significance of these polymorphisms might offer important leads for drug development and therapeutic applications. Brain imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provide the means to monitor the expression and function of many of these proteins in the living human brain. This paper reviews brain imaging studies designed to evaluate the significance of polymorphisms in genes coding for important drug targets (e.g., the serotonin transporter [SERT], the dopamine transporter [DAT] and the dopamine D(2) receptor) in terms of expression or function. These studies illustrate the unique opportunities, as well as the pitfalls, generated by combining genetic analysis with brain imaging studies.     

Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action

Advances in positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance spectroscopy (MRS), and the ability to label a wide variety of compounds for in vivo use in humans, have created a new technology for making precise physiological and pharmacological measurements. Due to the noninvasive nature of these approaches, repetitive and/or continuous measurements have become possible. Thus far, these techniques have been primarily used for one-time assessments of individuals. However, experience suggests that a major use of this technology will be in the evaluation of new drug therapies. Already, these techniques have been used to measure precisely and noninvasively the pharmacokinetics of a variety of antimicrobial, antineoplastic and CNS agents. In the case of CNS drugs, imaging techniques (particularly PET) have been used to define the classes of neuroreceptors with which the drug interacts. The physiological, pharmacological and biochemical measurements that can be performed noninvasively using modern imaging techniques can greatly facilitate the evaluation of new therapies. These measurements are most likely to be useful during drug development in preclinical studies and in phase I/II human studies. Preclinically, new drugs can be precisely compared with standard therapies, or a series of analogues can be screened for further development on the basis of performance in animal models. In Phase I/II, imaging measurements can be combined with classical pharmacokinetic data to establish optimal administration schedules, evaluate the utility of interventions in specific clinical situations, and aid in the design of Phase III trials.     

Recent advances in functional neuroimaging

Positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have been introduced into the field of brain science as an noninvasive approach to visualize brain function, focusing on the regional distribution of neuronal activity and its connectivity. Measurement of regional cerebral blood flow with PET has been established for mapping human brain function covering the whole brain with various task conditions. Recently introduced functional MRI technique can also detect the signal changes due to the local increase of blood flow by brain activation. Both PET and MRI provide similar activation patterns in cerebral cortical areas, and the study should be designed by considering the characteristics of each modality. Although PET continues to play a major role in imaging of the neurotransmission process, the efforts are now being made to apply this exciting technique to clinical diagnosis by means of single photon emission computed tomography (SPECT). Neuroreceptor imaging is now applied not only for differential diagnosis of neurological diseases but also for determination of optimal dose of appropriate therapeutic drugs in psychiatric patients. Combined use of activation studies with neurotransmission imaging will provide a new insight in understanding the brain mechanism of emotion and behavior.     

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).     

Nicotinic acetylcholine receptors and imaging

In vivo imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) offer the possibility to monitor human central nicotinic acetylcholine receptors (nAChRs) in a variety of central nervous system disorders. In the past, the only available PET radiotracer for imaging nAChRs in the human brain, [11C]-(-)-nicotine, suffered from a spectrum of not suitable properties for in vivo imaging. Current efforts are focused on the development of new, highly specific and highly selective radioligands based on different structural classes (e.g. nicotine, epibatidine, 3-pyridyl ether analogues) for central nAChRs. The most promising compounds are halogenated 3-pyridyl ether compounds for imaging alpha 4 beta 2 nAChRs. But there is still a lack for radiotracers for other subtypes of nicotinic acetylcholine receptors being a promising area of interest.     

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.     

Amino Acid transporter-targeted radiotracers for molecular imaging in oncology

Amino acids are required for sustenance of continuous uncontrolled growth of tumor cells, and upregulation of amino acid transporter expression has often been observed in tumor cells to facilitate their accelerated rates of amino acid uptake. Therefore, amino acid transporters have promise as ideal targets for tumor imaging. In fact, many natural and artificial amino acids have been radiolabeled for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging of tumor. In this article, we review the classification, molecular biology, and pharmacological relevance of amino acid transport systems. In addition, we discuss the chemistry, radiochemistry, current clinical applications, and future prospects for the use of radiolabeled amino acid-based probes for PET and SPECT imaging in oncology for each category of radionuclide.     

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.     

PET tracers for 5-HT(1A) receptors and uses thereof

The serotonin 5-HT(1A) receptor is implicated in the pathophysiology of major neuropsychiatric disorders, including depression, suicidal behavior, panic disorder, epilepsy, bulimia, schizophrenia, Parkinson's disease, and Alzheimer's disease and is, therefore, an important target for drug therapy. 5-HT(1A) receptors are expressed as somatodendritic autoreceptors in serotonin neurons of the raphé nuclei (presynaptic) and as postsynaptic receptors in cortical and subcortical serotonin terminal fields in the brain. Due to the higher concentration and heterogeneous distribution of this receptor, it is an attractive target for quantification in vivo using positron emission tomography (PET) and single photon emission tomography (SPECT). Here, we review the PET radioligands employed for imaging 5-HT(1A) receptors in living brain.     

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.