Current Topics in Medicinal Chemistry - Volume 10, Issue 15, 2010
Volume 10, Issue 15, 2010
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Editorial [Hot topic: Recent Advances in the Medicinal Radiochemistry of Radioligands for Cerebral In Vivo Imaging (Guest Editors: Andrew G. Horti and Robert F. Dannals)]
Authors: Andrew G. Horti and Robert F. DannalsMedicinal radiochemistry involves design, synthesis and evaluation of radiotracers for emission tomography imaging. The development of new radiotracers is based on the structure-imaging properties relationships, suitability for radiolabeling and safety properties. Medicinal radiochemistry emerged over the last three decades mainly as a result of the rapid advances in positron-emission tomography (PET) and single photon emission computed tomography (SPECT). Nowadays most medicinal chemistry journals publish PET radiochemistry papers and there are also a number of specialized journals available. Initially we planned to publish a single special issue in 2010 on recent advances in the development of in vivo radiotracers, but, because the enthusiastic response of the authors substantially exceeded the space of a single issue, we divided the articles between two issues. In special issue #15 entitled “ Recent advances in the medicinal radiochemistry of radioligands for cerebral in vivo imaging” there is a discussion of positron emission tomography radioligands for several receptors of central nervous system. In special issue #16 entitled “Current topics in the development of radioligands for positron-emission tomography imaging”, recent progress in the radioprobes for in vivo imaging of various non-central targets and advances in synthetic methodologies of PET radioligands is presented. Recent Advances in the Medicinal Radiochemistry of Radioligands for Cerebral In Vivo Imaging The first review of this issue (Finnema et al.) summarizes the present status of the D2/D3 receptor agonist PET radioligands. Evaluation of dopaminergic system with PET has grown significantly in the last two decades. Various PET radioligands are available for quantification of enzymes involved in dopamine synthesis and expression and function of reuptake proteins (VMAT and DAT). In addition, these radioligands are valuable research tools in the drug development because they allow, for example, measurement of the target occupancy. On the other side, DA receptor agonist radioligands that may be superior tools for measuring changes in endogenous dopamine levels are still under development. Another important CNS target, the serotonin transporter (SERT), plays a role in a variety of neuropsychiatric disorders including depression, schizophrenia, substance abuse, alcoholism, and Alzheimer's disease. The comprehensive review of Huang et al. describes the history of development and validation of effective SERT radiotracers for PET/SPECT imaging in the last twenty years. Development of radioligands for a relatively new target for PET imaging, the cannabinoid receptor subtype 2 (CB2R), is presented in the Evens and Bormans paper. The CB2R is mainly found in tissues and organs related to the immune system. However, in pathological conditions, including neuroinflammation, a strong upregulation has been observed in brain tissue. If a quality CB2 radioligand for PET becomes available it may provide an opportunity for diagnostic, drug development and therapy evaluation of various neurodegenerative and inflammatory brain disorders. The paper of Toyohara et al. reviews recent development of elusive radioligands for in vivo imaging of α7 nicotinic acetylcholine receptors (α7-nAChRs). The PET imaging community is eager to obtain a quality α7-nAChRs radioligand for a number of important applications including schizophrenia, Alzheimer's disease, anxiety, depression, and drug addiction. However, these radioligands have been difficult to develop and only the latest studies have demonstrated progress toward the practical α7-nAChR radioligands. The paper of the scientists from Zurich (Mu et al.) describes the history of radioligands for PET imaging of the metabotropic glutamate receptor subtype 5 (mGluR5). Modulation of mGluR5s has potential for the treatment of variety of psychiatric and neurological diseases such as depression, anxiety, schizophrenia and Parkinson's disease. The vesicular acetylcholine transporter (VAChT) is a highly attractive target for PET imaging of the earlier stages of Alzheimer's disease. Giboureau et al. summarizes the latest attempts to identify a suitable VAChT PET radioligand. Although several promising radioligands have been synthesized, further validation is required to confirm their clinical usefulness.
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Current State of Agonist Radioligands for Imaging of Brain Dopamine D2/D3 Receptors In Vivo with Positron Emission Tomography
Authors: Sjoerd J. Finnema, Benny Bang-Andersen, Hakan V. Wikstrom and Christer HalldinDopamine (DA) is known to play an important role in numerous brain functions and has been suggested to be involved in several neuropsychiatric and neurological disorders. From early on, positron emission tomography (PET) studies of the DA system have yielded high interest. Currently, several aspects of the functionality of DA neurons can be imaged, including the DA synthesis rate and the expression of DA-related proteins (receptors and transporters). A more recent application of radioligands targeting DA receptors is to study the endogenous neurotransmitter levels in vivo in brain. In vitro binding studies have suggested that in general DA receptors, as many other G-protein coupled receptors, exist in two affinity states for agonist binding. The high affinity state is thought to represent the functional state of the receptor, and the proportion between high and low affinity states may change with the development of disease. PET imaging with agonist radioligands may provide information on the existence of the high affinity state in vivo. In addition, DA receptor agonist radioligands may be superior tools for measuring changes in endogenous DA levels as antagonist radioligands inherently bind to both the low and the high affinity state. This review primarily summarizes the current status of agonist PET radioligands targeting the D2 and D3 receptor (D2/D3 receptor). In addition several PET studies evaluating the utility of the agonist concept are discussed.
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Development of Effective PET and SPECT Imaging Agents for the Serotonin Transporter: Has a Twenty-Year Journey Reached its Destination?
Authors: Yiyun Huang, Ming-Qiang Zheng and John M. GerdesThe serotonin transporter (SERT) has been implicated in a variety of neuropsychiatric disorders including depression, schizophrenia, substance abuse, alcoholism, and Alzheimer's disease. Radiotracer-based in vivo imaging techniques such as Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) are important tools to investigate the functions of SERT in the living brain under normal conditions and its dysfunction in diseases. In this report we review the development and validation of effective PET and SPECT radiotracers in the last twenty years. First, the requirements for an effective imaging tracer, and factors influencing a tracer's in vivo imaging performance are discussed. PET and SPECT radiotracers for SERT are then categorized and reviewed according to their chemical scaffolds: 1) SSRIs and related compounds; 2) tropane-based ligands; 3) isoquinolines; and 4) substituted diarylsulfides. Critical evaluation and comments are provided for promising radiotracers, if any, emerging from each chemical scaffold. Based on experimental data gathered from radiotracer development for SERT, an examination of the relationship between an imaging tracer's in vitro physicochemical and pharmacological properties and its in vivo performance parameters is provided. Finally, tracers available for imaging applications in humans are assessed and compared in terms of tissue binding kinetics, non-specific binding, and specific binding signals in vivo. From these assessments, we conclude that, after twenty years of development efforts, a number of effective PET and SPECT radiotracers have now been validated and are available for imaging SERT in humans. The applications of these efficacious SERT imaging agents will further advance our understanding of this important transporter in psychiatric and neurodegenerative disorders.
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Non-Invasive Imaging of the Type 2 Cannabinoid Receptor, Focus on Positron Emission Tomography
Authors: Nele Evens and Guy M. BormansThe type 2 cannabinoid receptor (CB2R) is a relatively new target for drug development, as the receptor was only discovered in 1993. The CB2R is mainly expressed in tissues and organs related to the immune system. However, in pathological conditions, mostly inflammatory, a strong upregulation has been observed. Because of its expression in activated microglia, the type 2 cannabinoid receptor might play an important role in pathologies with a neuroinflammatory component. Positron emission tomography provides a sensitive non-invasive imaging technique to study and quantify receptor expression. In this review, the importance of CB2R imaging, the current status and the future possibilities for the development of CB2R PET radioligands are discussed.
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Recent Development of Radioligands for Imaging α7 Nicotinic Acetylcholine Receptors in the Brain
Authors: Jun Toyohara, Jin Wu and Kenji HashimotoThe α7 nicotinic acetylcholine receptors (nAChRs), ligand-gated Ca2+ channels composed of homopentamers of α7 subunits, represent the most abundant with α4β2 nAChRs in the brain. Several lines of evidence suggest that α7 nAChRs play a role in the physiology of neuropsychiatric diseases such as schizophrenia, Alzheimer's disease, anxiety, depression, and drug addiction; hence, α7 nAChRs seem to be attractive therapeutic targets for these diseases. Several researchers have attempted to develop radioligands that can be used to selectively and quantitatively examine the distribution of α7 nAChRs in the human brain with positron emission tomography (PET) or single photon emission tomography (SPECT). Although efforts are underway, very low density of α7 nAChR and scarcity of very high affinity ligands hamper the development of α7 subtype-selective radioligands for in vivo imaging. In this article, we review the recent topics on the development of PET/SPECT ligands for in vivo imaging of α7 nAChRs in the brain.
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Radioligands for the PET Imaging of Metabotropic Glutamate Receptor Subtype 5 (mGluR5)
Authors: Linjing Mu, P. August Schubiger and Simon M. AmetameyMetabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCR), which activate intracellular secondary messenger systems when bound by the physiological ligand glutamate. Modulation of mGluR5s has potential for the treatment of variety of psychiatric and neurological diseases such as depression, anxiety, schizophrenia and Parkinson's disease. Positron emission tomography (PET) might offer the possibility to visualize the mGluR5 and present an interesting tool for studying this receptor-subtype under physiologic and pathologic conditions. In this review paper, emphasis is given to the radiosynthesis, in vitro and in vivo characterization of recently published mGluR5 PET tracers.
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PET Radioligands for the Vesicular Acetylcholine Transporter (VAChT)
The vesicular acetylcholine transporter (VAChT) is a glycoprotein responsible for the accumulation of acetylcholine into pre-synaptic vesicules of cholinergic neurons. Cholinergic innervation has been shown to be decreased at the earlier stages of Alzheimer's disease (AD). Thus, the expression of VAChT has been correlated with the severity of the dementia and has been considered as a significant diagnostic target for AD. To this end numerous radioligands based on the vesamicol scaffold have been developed for imaging the VAChT using positron emission tomography (PET). Among the various radioligands only a small number have been evaluated in vivo in non-human primate and human. Despite promising in vitro, ex vivo and first in vivo studies, most of them are unsuitable for clinical use in humans due to poor selectivity over σ receptors, low extraction from the blood, slow brain kinetics or fast metabolism. To date (-)-[11C]OMV (1), (-)-[11C]MABV (2), (-)-[18F]-FEOBV (6), (-)-trans-2-hydroxy-3-(4-(4-[18F]fluorobenzoyl)piperidine) tetralin (8) and [18F]FBMV (12) are promising radioligands for the VAChT, though further validation is required to confirm their clinical usefulness.
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Volumes & issues
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Volume 25 (2025)
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Volume (2025)
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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