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Nuclear Imaging Techniques for New Drug Development
NUCLEAR PHARMACY
Nuclear Imaging Techniques for New Drug Development Nuclear imaging techniques are adding to our understanding of the actions ofpharmaceutical agents.
Nuclear imaging techniques, such as positron emission tomography (PET), are helping researchers identify the effects of pharmaceutical agents on a variety of in vivo systems. Such techniques involve labeling the agent of interest with a radioactive atom (e.g., fluorine-I8 [l8F] or carbon-II [llC]), or using radioactive water (H215 0) or a glucose analogue (fluorodeoxyglucose [18FDGD. Because these substances decay by emitting positrons, scanners can be used to obtain cross-sectional images of the quantitative distribution of radioactivity in the body. From these images, mathematical models are used to generate physiologic measurements such as blood flow, glucose metabolism, and neurotransmitter or neuroreceptor activity.
Mapping the Actions of Psychoactive Medications Peter Herscovitch, MD, noted that PET has been used extenively to study the effects of medications on the brain. In the brain, both regional cerebral blood flow (rCBF) and the regional cerebral metabolic rate of glucose increase during periods of increased neuronal activity. Therefore, measurements of these parameters can be used to determine which areas of the brain exhibit changes in activity during specific tasks, with exposure to p ychoactive ubstances, or in patients with neuropsychiatric disea e . Such techniques can be used to identify the time course of the action of a medication and to investigate the effects of antagonists on medication actions. Data gained from these studies can help elucidate the mechanisms of action underlying various therapeutic and toxic effects of medications. Based on presentations by Peter Herscovitch, MD, FRCPC, FACP, chief, PET Imaging Section, National Institutes of Health, Bethesda, Md.; and Edward M. Bednarczyk, PharmD, research assistant professor of pharmacy practice and nuclear medicine, Departments of Pharmacy Practice and Nuclear Medicine, University of Buffalo, State University of New York, Buffalo.
S64
Supplement to the Journal of the American PhannaceuticaJ Association
However, when studying the functional impact of medications on neuronal activity, it is important to note that changes in rCBF and glucose metabolism may be seen in areas to which affected neurons project instead of the actual site of action. Thus, it is possible to obtain information about entire neuronal pathways or systems affected by the drug. For example, benzodiazepines (e.g., lorazepam) produce time- and dose-dependent changes in both rCBF and behavioral and mood parameters. Following administration of lorazepam, the greatest changes in rCBF are noted in the thalamus. However, the greatest concentration of benzodiazepine receptors is in the cerebral cortex. Therefore, the greatest effects of benzodiazepines occur downstream from their actual site of action (i.e., at the site of distant neuronal projections). Functional changes identified during PET studies have been closely correlated with the clinical effects of various medications. Interestingly, PET studies of selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine) have found different effects in responders and nonresponders. When SSRIs are used in the treatment of major depression, approximately 6 weeks of therapy are required before a clinical improvement is noted. Studies of regional glucose metabolism have found that metabolic changes are closely correlated with the clinical response. One week after the initiation of therapy (when no clinical effects are seen), fluoxetine is associated with increased metabolism in the pons, globus pallidus, hippocampus, and some cortical areas, and decreased metabolism is observed in the caudate, thalamus, and parahippocampus. Following 6 weeks of therapy, responders demonstrate a new pattern of glucose metabolism while nonresponders have the same pattern seen after 1 week of therapy. Thus, lateoccurring changes that result from fluoxetine mirror clinical responses and demonstrate a change in brain circuitry. Moreover, these changes only occur in individuals who respond to treatment. Changes in rCBF and the glucose metabolism that correlate with clinical effects (both therapeutic and toxic) have been noted with a variety of other psychoactive agents, including dopaminergic agents, cholinergic agents, anticonvulsants, piracetam, and the
September/October 2001
Vol. 41, No.5, Suppl. 1
Nuclear Imaging Techniques for New Drug Development
illegal stimulant MDMA (3,4-methylenedioxy-N-methamphetamine; "ecstasy").
Other Applications for Functional Imaging Nuclear imaging techniques also have applications for a variety of other in vivo systems. Edward M. Bednarczyk, PharmD, described techniques that can be used to investigate the biodistribution of a medication, the effects on blood flow or metabolism in other tissues (including cardiac tissue, renal tissue, and malignant tissue), and effects of a medication on organ function. For example, radiolabeling of triamcinolone acetonide has helped to describe the biodistribution of this corticosteroid following intranasal application. Such techniques allow investigation of the anatomic distribution of the medication, as well as changes in distribution over time. Data from these studies, when combined with anatomic stereotactic information, have been used to describe the functional effects of this drug. Imaging techniques also appear to have unique applications for the study of subjective conditions that are difficult to quantify clinically (e.g., migraine headaches and tinnitus). These techniques may be particularly useful for studying conditions in which the underlying pathophysiology is poorly understood, because they can help identify regions that experience functional modification during treatment and lead to a greater explanation of the underlying disease process. Measurement of blood flow can be applied to evaluation of medications expected to change blood flow. Dr. Bednarczyk presented data from two studies of sumatriptan in migraine headache. Quantitative cerebral blood flow measurements from spontaneous migraine and nitroglycerin-induced headache were presented, along with qualitative regional data demonstrating the sensitivity of these tools in measuring drug effects. Tumor responses to chemotherapy may also be assessed with nuclear imaging techniques. Currently, patients often require surgery to determine whether a chemotherapeutic regimen has been successful. However, in addition to the risks and discomfort associated with surgery, most chemotherapy courses require several months of treatment during which an ineffective course of therapy may be continued while the tumor is advancing. Dr. Bednarczyk reviewed data from recent nuclear imaging studies that found a reduction of glucose metabolism in tumors that respond to chemotherapy at 6 weeks. (Interestingly, increased activity was observed 1 week following therapy, possibly due to the tumor's cellular repair mechanisms.) Thus, the possibility exists that, in the future, imaging modalities could largely replace
Vol. 41, No.5, Su
I. 1
September/October 2001
NUCLEAR PHARMACY
the use of exploratory urgery a a mean of investigating the efficacy of a chemotherapeutic regimen. However, the utility of performing imaging tudie at various time points during a chemotherapy regimen require further clarification and is an area of ongoing research.
Functional Imaging and the Future of Drug Development Nuclear imaging techniques have a wide range of current and potential applications for new drug development. For example, if a specific functional response is known to be associated with a desired clinical response, preclinical or early clinical investigations can determine whether the investigational agent produces the desired functional response. The presence of a functional response could be used to screen for agents most likely to produce desired results in clinical trials and remove ineffective compounds, thereby shortening drug-development times and costs. However, many formidable barriers remain to the use of imaging techniques to predict clinical responses. For example, these techniques are not universally applicable-not all medications are conducive to radiolabeling and others have distribution half-lives that are much longer than the decay half-life of available radiotracers (which prevents generation of accurate biodistribution data). In addition, all results seen in functional imaging studies are surrogate markers of the ultimate desired clinical effect. Therefore, it must be conclusively demonstrated that images are representative of the clinical effects. Extensive validation work must be performed before these techniques become widely used in drug development, particularly if pharmaceutical companies plan to present data on surrogate markers to the U.S. Food and Drug Administration as components of new drug applications.
Summary • Nuclear imaging techniques are being used in studies to illuminate how psychoactive medications affect the brain. • Functional effects observed in PET scans can be correlated with both therapeutic and toxic effects of medications. • Imaging techniques may be particularly effective for studying conditions that are difficult to quantify by objective clinical criteria. • These techniques may eventually streamline the drug development process, but validation of the utility of clinical markers must be performed first. This symposium was made possible by an unrestricted educational grant from Syncor International Corporation.
Supplement to the Journal of the American Phannaceutical Association
S65
Nuclear Imaging Techniques for New Drug Development Nuclear imaging techniques are adding to our understanding of the actions ofpharmaceutical agents.
Nuclear imaging techniques, such as positron emission tomography (PET), are helping researchers identify the effects of pharmaceutical agents on a variety of in vivo systems. Such techniques involve labeling the agent of interest with a radioactive atom (e.g., fluorine-I8 [l8F] or carbon-II [llC]), or using radioactive water (H215 0) or a glucose analogue (fluorodeoxyglucose [18FDGD. Because these substances decay by emitting positrons, scanners can be used to obtain cross-sectional images of the quantitative distribution of radioactivity in the body. From these images, mathematical models are used to generate physiologic measurements such as blood flow, glucose metabolism, and neurotransmitter or neuroreceptor activity.
Mapping the Actions of Psychoactive Medications Peter Herscovitch, MD, noted that PET has been used extenively to study the effects of medications on the brain. In the brain, both regional cerebral blood flow (rCBF) and the regional cerebral metabolic rate of glucose increase during periods of increased neuronal activity. Therefore, measurements of these parameters can be used to determine which areas of the brain exhibit changes in activity during specific tasks, with exposure to p ychoactive ubstances, or in patients with neuropsychiatric disea e . Such techniques can be used to identify the time course of the action of a medication and to investigate the effects of antagonists on medication actions. Data gained from these studies can help elucidate the mechanisms of action underlying various therapeutic and toxic effects of medications. Based on presentations by Peter Herscovitch, MD, FRCPC, FACP, chief, PET Imaging Section, National Institutes of Health, Bethesda, Md.; and Edward M. Bednarczyk, PharmD, research assistant professor of pharmacy practice and nuclear medicine, Departments of Pharmacy Practice and Nuclear Medicine, University of Buffalo, State University of New York, Buffalo.
S64
Supplement to the Journal of the American PhannaceuticaJ Association
However, when studying the functional impact of medications on neuronal activity, it is important to note that changes in rCBF and glucose metabolism may be seen in areas to which affected neurons project instead of the actual site of action. Thus, it is possible to obtain information about entire neuronal pathways or systems affected by the drug. For example, benzodiazepines (e.g., lorazepam) produce time- and dose-dependent changes in both rCBF and behavioral and mood parameters. Following administration of lorazepam, the greatest changes in rCBF are noted in the thalamus. However, the greatest concentration of benzodiazepine receptors is in the cerebral cortex. Therefore, the greatest effects of benzodiazepines occur downstream from their actual site of action (i.e., at the site of distant neuronal projections). Functional changes identified during PET studies have been closely correlated with the clinical effects of various medications. Interestingly, PET studies of selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine) have found different effects in responders and nonresponders. When SSRIs are used in the treatment of major depression, approximately 6 weeks of therapy are required before a clinical improvement is noted. Studies of regional glucose metabolism have found that metabolic changes are closely correlated with the clinical response. One week after the initiation of therapy (when no clinical effects are seen), fluoxetine is associated with increased metabolism in the pons, globus pallidus, hippocampus, and some cortical areas, and decreased metabolism is observed in the caudate, thalamus, and parahippocampus. Following 6 weeks of therapy, responders demonstrate a new pattern of glucose metabolism while nonresponders have the same pattern seen after 1 week of therapy. Thus, lateoccurring changes that result from fluoxetine mirror clinical responses and demonstrate a change in brain circuitry. Moreover, these changes only occur in individuals who respond to treatment. Changes in rCBF and the glucose metabolism that correlate with clinical effects (both therapeutic and toxic) have been noted with a variety of other psychoactive agents, including dopaminergic agents, cholinergic agents, anticonvulsants, piracetam, and the
September/October 2001
Vol. 41, No.5, Suppl. 1
Nuclear Imaging Techniques for New Drug Development
illegal stimulant MDMA (3,4-methylenedioxy-N-methamphetamine; "ecstasy").
Other Applications for Functional Imaging Nuclear imaging techniques also have applications for a variety of other in vivo systems. Edward M. Bednarczyk, PharmD, described techniques that can be used to investigate the biodistribution of a medication, the effects on blood flow or metabolism in other tissues (including cardiac tissue, renal tissue, and malignant tissue), and effects of a medication on organ function. For example, radiolabeling of triamcinolone acetonide has helped to describe the biodistribution of this corticosteroid following intranasal application. Such techniques allow investigation of the anatomic distribution of the medication, as well as changes in distribution over time. Data from these studies, when combined with anatomic stereotactic information, have been used to describe the functional effects of this drug. Imaging techniques also appear to have unique applications for the study of subjective conditions that are difficult to quantify clinically (e.g., migraine headaches and tinnitus). These techniques may be particularly useful for studying conditions in which the underlying pathophysiology is poorly understood, because they can help identify regions that experience functional modification during treatment and lead to a greater explanation of the underlying disease process. Measurement of blood flow can be applied to evaluation of medications expected to change blood flow. Dr. Bednarczyk presented data from two studies of sumatriptan in migraine headache. Quantitative cerebral blood flow measurements from spontaneous migraine and nitroglycerin-induced headache were presented, along with qualitative regional data demonstrating the sensitivity of these tools in measuring drug effects. Tumor responses to chemotherapy may also be assessed with nuclear imaging techniques. Currently, patients often require surgery to determine whether a chemotherapeutic regimen has been successful. However, in addition to the risks and discomfort associated with surgery, most chemotherapy courses require several months of treatment during which an ineffective course of therapy may be continued while the tumor is advancing. Dr. Bednarczyk reviewed data from recent nuclear imaging studies that found a reduction of glucose metabolism in tumors that respond to chemotherapy at 6 weeks. (Interestingly, increased activity was observed 1 week following therapy, possibly due to the tumor's cellular repair mechanisms.) Thus, the possibility exists that, in the future, imaging modalities could largely replace
Vol. 41, No.5, Su
I. 1
September/October 2001
NUCLEAR PHARMACY
the use of exploratory urgery a a mean of investigating the efficacy of a chemotherapeutic regimen. However, the utility of performing imaging tudie at various time points during a chemotherapy regimen require further clarification and is an area of ongoing research.
Functional Imaging and the Future of Drug Development Nuclear imaging techniques have a wide range of current and potential applications for new drug development. For example, if a specific functional response is known to be associated with a desired clinical response, preclinical or early clinical investigations can determine whether the investigational agent produces the desired functional response. The presence of a functional response could be used to screen for agents most likely to produce desired results in clinical trials and remove ineffective compounds, thereby shortening drug-development times and costs. However, many formidable barriers remain to the use of imaging techniques to predict clinical responses. For example, these techniques are not universally applicable-not all medications are conducive to radiolabeling and others have distribution half-lives that are much longer than the decay half-life of available radiotracers (which prevents generation of accurate biodistribution data). In addition, all results seen in functional imaging studies are surrogate markers of the ultimate desired clinical effect. Therefore, it must be conclusively demonstrated that images are representative of the clinical effects. Extensive validation work must be performed before these techniques become widely used in drug development, particularly if pharmaceutical companies plan to present data on surrogate markers to the U.S. Food and Drug Administration as components of new drug applications.
Summary • Nuclear imaging techniques are being used in studies to illuminate how psychoactive medications affect the brain. • Functional effects observed in PET scans can be correlated with both therapeutic and toxic effects of medications. • Imaging techniques may be particularly effective for studying conditions that are difficult to quantify by objective clinical criteria. • These techniques may eventually streamline the drug development process, but validation of the utility of clinical markers must be performed first. This symposium was made possible by an unrestricted educational grant from Syncor International Corporation.
Supplement to the Journal of the American Phannaceutical Association
S65