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Vassilios Papadopoulos - One of the best experts on this subject based on the ideXlab platform.
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Translocator Protein and new targets for neuroinflammation
Clinical and Translational Imaging, 2015Co-Authors: Marisol Herrera-rivero, Michael T. Heneka, Vassilios PapadopoulosAbstract:The mitochondrial Translocator Protein (18 kDa; TSPO) is involved in a wide array of physiological processes importantly including cholesterol transport, steroidogenesis and immunomodulation. In the central nervous system (CNS), TSPO expression regionally increases in glial cells upon brain insult with a differential pattern suggestive of cell-specific functions in inflammation and repair. These properties have made TSPO a valuable marker to assess the state, and progression of diverse neurological and psychiatric conditions, including traumatic brain injury, stroke, neurodegenerative diseases, anxiety, depression and schizophrenia. In the past years, an increasing number of radiolabeled TSPO ligands for the visualization and quantification of TSPO through positron emission tomography (PET), single-photon emission tomography (SPECT) and magnetic resonance imaging (MRI) have been developed in the pursuit of higher sensitivity and specificity for clinical applications. However, TSPO is not the only molecule holding great potential as an imaging marker of neuroinflammation; cell adhesion molecules, such as VCAM-1 and ICAM-1, the myeloperoxidase, matrix metalloProteinases, the cannabinoid receptor 2 (CB2), P2X7, cyclooxygenase 1 (COX-1), free radicals and leukocyte populations have also been subjects of study as targets to image inflammatory processes in the injured or diseased brain. In this review, we present the most relevant aspects of TSPO molecular features that fundament its imaging applications in the context of neuroinflammation, and comment on the development of imaging agents and strategies targeting TSPO as well as other molecules and cells implicated in inflammatory processes.
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Translocator Protein pharmacology and steroidogenesis
Biochemical Society Transactions, 2015Co-Authors: Andrew Midzak, Barry R Zirkin, Vassilios PapadopoulosAbstract:The Translocator Protein (TSPO; 18k Da) is an evolutionarily conserved outer mitochondrial membrane (OMM) Protein highly expressed in steroid-synthesizing cells and found to possess a number of physiological and drug-binding partners. Extensive pharmacological, biochemical and cell biological research over the years has led to a model of TSPO involvement in mitochondrial cholesterol transport and promotion of steroid synthesis, a model guiding the design of drugs useful in stimulating neurosteroid synthesis and alleviating psychopathological symptoms. The involvement of TSPO in these processes has been called into question; however, with the publication of TSPO-deletion mouse models which saw no changes in steroid production. Here, we review work characterizing TSPO in steroidogenesis and offer perspective to research into TSPO pharmacology and its involvement in steroid biosynthesis.
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on the role of the Translocator Protein 18 kda tspo in steroid hormone biosynthesis
Endocrinology, 2014Co-Authors: Vassilios PapadopoulosAbstract:Morohaku et al (1) report that the Translocator Protein (18-kDa) TSPO, previously known as peripheraltype benzodiazepine receptor, is not required for steroid hormone biosynthesis. The study was based on analysis of a conditional knockout of TSPO in Leydig and Sertoli cells. The findings were surprising and were coupled to a definitive statement implying that what was suggested for Leydig cells is the case for all steroid-synthesizing cells in the body (1). To understand the reported findings and place them within the context of the TSPO and steroidogenesis literature, I will try to address five questions: 1) What are the complexities of cholesterol mobilization and transport? 2) What are the data indicating that TSPO is integrally involved in steroid formation? 3) Are there limitations of the Morohaku paper? 4) Where do the discrepancies lie? and 5) Where do we go from here?
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Role of Translocator Protein in melanoma growth and progression
Archives of Dermatological Research, 2012Co-Authors: Tatiana Ruksha, Maria Aksenenko, Vassilios PapadopoulosAbstract:The 18 kDa Translocator Protein (TSPO) is a primarily mitochondrial Protein that participates in steroid biosynthesis, cell proliferation, differentiation, apoptosis, and the regulation of mitochondrial function in general. TSPO has been implicated in carcinogenesis via its ability to transport cholesterol into mitochondria to meet the increased energy needs of tumor cells. The purpose of this study was to investigate TSPO involvement in melanoma pathogenesis. TSPO expression in melanoma and melanocytic nevi was analyzed by immunohistochemistry and real-time PCR, and TSPO levels were correlated to the invasiveness of the tumor. The number of TSPO-positive melanoma samples increased with tumor progression irrespective of age or gender of patients. Similar findings were obtained while examining TSPO expression levels in relation to the Clark invasion stage of the tumor. Indeed, the immunohistochemical index was elevated in invasive tumors characterized as Clark level V compared to those characterized as levels I and II. Besides, the elevation of immunohistochemical index was accompanied with a shift of homogeneous cytoplasmic subcellular expression pattern of the Protein to nuclear and perinuclear. Taken together, these results suggest TSPO participation in melanoma growth and progression.
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Translocator Protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders
Nature reviews. Drug discovery, 2010Co-Authors: Rainer Rupprecht, Jinjiang Fan, Vassilios Papadopoulos, Gerhard Rammes, Thomas C. Baghai, Nagaraju Akula, Ghislaine Groyer, David H. Adams, Michael SchumacherAbstract:The Translocator Protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders.
Andrew Sutherland - One of the best experts on this subject based on the ideXlab platform.
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Structure–activity relationships of novel iodinated quinoline-2-carboxamides for targeting the Translocator Protein
MedChemComm, 2013Co-Authors: Adele Blair, Louise Stevenson, Deborah Dewar, Sally L. Pimlott, Andrew SutherlandAbstract:In an effort to develop a new SPECT imaging agent for the Translocator Protein (TSPO), a series of novel iodinated quinoline-2-carboxamides have been synthesised and evaluated for binding affinity using rat brain homogenates. The outcome of the biological testing in combination with HPLC determination of the physicochemical properties of these compounds directed the design of new analogues resulting in 4-(2-iodophenyl)quinoline-2-N-diethylcarboxamide, a new TSPO ligand with higher affinity than the widely used clinical imaging agent PK11195.
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New SPECT imaging agents for the Translocator Protein
NeuroImage, 2010Co-Authors: Andrew Sutherland, Louise Stevenson, Adriana Tavares, Deborah Dewar, Sally L. PimlottAbstract:During the course of the studies outlined in this thesis, a new short and efficient synthesis of PK11195 was developed using Pd(0)-mediated reactions to effect the key carbon-carbon bond forming reactions. PK11195 is a ligand that interacts with the Translocator Protein(TSPO) in the brain. During brain injury the concentration of TSPO increases, making TSPO an ideal and sensitive biomarker. Using single photon emission computed tomography along with [123I]PK11195, medical practitioners are able to visualize the receptor. In addition to the synthesis of PK11195, three other analogues were devised using the same methodology as for PK11195. Firstly, a Heck reaction was used to form the isoquinoline core, followed by a Suzuki reaction to couple the correct phenyl ring.
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New iodinated quinoline-2-carboxamides for SPECT imaging of the Translocator Protein
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Louise Stevenson, Adriana Tavares, Aurélie Brunet, Fiona I. Mcgonagle, Deborah Dewar, Sally L. Pimlott, Andrew SutherlandAbstract:Abstract With the aim of developing new SPECT imaging agents for the Translocator Protein (TSPO), a small library of iodinated quinoline-2-carboxamides have been prepared and tested for binding affinity with TSPO. N,N-Diethyl-3-iodomethyl-4-phenylquinoline-2-carboxamide was found to have excellent affinity (Ki 12.0 nM), comparable to that of the widely used TSPO imaging agent PK11195.
Claudia Martini - One of the best experts on this subject based on the ideXlab platform.
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Translocator Protein and steroidogenesis
Biochemical Journal, 2018Co-Authors: Barbara Costa, Eleonora Da Pozzo, Claudia MartiniAbstract:Two interesting papers by Barren et al. and Owen et al. have been very recently published in Biochemical Journal , reporting the role of Translocator Protein (TSPO) in steroidogenesis. The involvement of TSPO in the steroid biosynthesis has been suggested by 30 years of researches, using biochemical, pharmacological and genetic experimental approaches. In the last 3 years, however, the TSPO involvement in steroidogenesis has been intensively and profoundly discussed. Using in vivo genetic manipulations aimed at deleting TSPO, some researchers have excluded its role in steroid production. Other research groups, using similar genetic manipulation techniques, have presented different results, corroborating the role of TSPO in steroidogenesis, in particular, when hormonal stimulation occurs. In this scenario, the publications by Barron et al. about ‘Steroidogenic abnormalities in Translocator Protein knockout mice and significance in the aging male’ and by Owen et al. about ‘TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis’ are part of this debate and provide further and more accurate information supporting the importance of TSPO as a steroidogenesis regulator.
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Targeting the 18-kDa Translocator Protein: recent perspectives for neuroprotection.
Biochemical Society transactions, 2015Co-Authors: Eleonora Da Pozzo, Barbara Costa, Chiara Giacomelli, Elisabetta Barresi, Sabrina Taliani, Federico Da Settimo Passetti, Claudia MartiniAbstract:The Translocator Protein (TSPO, 18 kDa), mainly localized in the outer mitochondrial membrane of steroidogenic tissues, is involved in several cellular functions. TSPO level alterations have been reported in a number of human disorders, particularly in cancer, psychiatric and neurological diseases. In the central nervous system (CNS), TSPO is usually expressed in glial cells, but also in some neuronal cell types. Interestingly, the expression of TSPO on glial cells rises after brain injury and increased TSPO expression is often observed in neurological disorders, gliomas, encephalitis and traumatic injury. Since TSPO is up-regulated in brain diseases, several structurally different classes of ligands targeting TSPO have been described as potential diagnostic or therapeutic agents. Recent researches have reported that TSPO ligands might be valuable in the treatment of brain diseases. This review focuses on currently available TSPO ligands, as useful tools for the treatment of neurodegeneration, neuro-inflammation and neurotrauma.
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Ether analogues of DPA-714 with subnanomolar affinity for the Translocator Protein (TSPO)
European journal of medicinal chemistry, 2015Co-Authors: Samuel D. Banister, Eleonora Da Pozzo, Claudia Martini, Corinne Beinat, Shane M. Wilkinson, Bin Shen, Cecilia Bartoli, Silvia Selleri, Frederick T. Chin, Michael KassiouAbstract:Sixteen new phenyl alkyl ether derivatives (12, 14e28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [ 3 H] PK11195 using 18 kDa Translocator Protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki ¼ 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134e331% above baseline) in a rat C6 glioma cell steroidogenesis assay. © 2015 Published by Elsevier Masson SAS.
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Translocator Protein (TSPO) and neurosteroids: implications in psychiatric disorders
Current molecular medicine, 2012Co-Authors: E Da Pozzo, Barbara Costa, Claudia MartiniAbstract:The Translocator Protein (TSPO) is a five transmembrane domain Protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans. The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders.
Louise Stevenson - One of the best experts on this subject based on the ideXlab platform.
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Structure–activity relationships of novel iodinated quinoline-2-carboxamides for targeting the Translocator Protein
MedChemComm, 2013Co-Authors: Adele Blair, Louise Stevenson, Deborah Dewar, Sally L. Pimlott, Andrew SutherlandAbstract:In an effort to develop a new SPECT imaging agent for the Translocator Protein (TSPO), a series of novel iodinated quinoline-2-carboxamides have been synthesised and evaluated for binding affinity using rat brain homogenates. The outcome of the biological testing in combination with HPLC determination of the physicochemical properties of these compounds directed the design of new analogues resulting in 4-(2-iodophenyl)quinoline-2-N-diethylcarboxamide, a new TSPO ligand with higher affinity than the widely used clinical imaging agent PK11195.
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New SPECT imaging agents for the Translocator Protein
NeuroImage, 2010Co-Authors: Andrew Sutherland, Louise Stevenson, Adriana Tavares, Deborah Dewar, Sally L. PimlottAbstract:During the course of the studies outlined in this thesis, a new short and efficient synthesis of PK11195 was developed using Pd(0)-mediated reactions to effect the key carbon-carbon bond forming reactions. PK11195 is a ligand that interacts with the Translocator Protein(TSPO) in the brain. During brain injury the concentration of TSPO increases, making TSPO an ideal and sensitive biomarker. Using single photon emission computed tomography along with [123I]PK11195, medical practitioners are able to visualize the receptor. In addition to the synthesis of PK11195, three other analogues were devised using the same methodology as for PK11195. Firstly, a Heck reaction was used to form the isoquinoline core, followed by a Suzuki reaction to couple the correct phenyl ring.
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New iodinated quinoline-2-carboxamides for SPECT imaging of the Translocator Protein
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Louise Stevenson, Adriana Tavares, Aurélie Brunet, Fiona I. Mcgonagle, Deborah Dewar, Sally L. Pimlott, Andrew SutherlandAbstract:Abstract With the aim of developing new SPECT imaging agents for the Translocator Protein (TSPO), a small library of iodinated quinoline-2-carboxamides have been prepared and tested for binding affinity with TSPO. N,N-Diethyl-3-iodomethyl-4-phenylquinoline-2-carboxamide was found to have excellent affinity (Ki 12.0 nM), comparable to that of the widely used TSPO imaging agent PK11195.
Sally L. Pimlott - One of the best experts on this subject based on the ideXlab platform.
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Structure–activity relationships of novel iodinated quinoline-2-carboxamides for targeting the Translocator Protein
MedChemComm, 2013Co-Authors: Adele Blair, Louise Stevenson, Deborah Dewar, Sally L. Pimlott, Andrew SutherlandAbstract:In an effort to develop a new SPECT imaging agent for the Translocator Protein (TSPO), a series of novel iodinated quinoline-2-carboxamides have been synthesised and evaluated for binding affinity using rat brain homogenates. The outcome of the biological testing in combination with HPLC determination of the physicochemical properties of these compounds directed the design of new analogues resulting in 4-(2-iodophenyl)quinoline-2-N-diethylcarboxamide, a new TSPO ligand with higher affinity than the widely used clinical imaging agent PK11195.
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New SPECT imaging agents for the Translocator Protein
NeuroImage, 2010Co-Authors: Andrew Sutherland, Louise Stevenson, Adriana Tavares, Deborah Dewar, Sally L. PimlottAbstract:During the course of the studies outlined in this thesis, a new short and efficient synthesis of PK11195 was developed using Pd(0)-mediated reactions to effect the key carbon-carbon bond forming reactions. PK11195 is a ligand that interacts with the Translocator Protein(TSPO) in the brain. During brain injury the concentration of TSPO increases, making TSPO an ideal and sensitive biomarker. Using single photon emission computed tomography along with [123I]PK11195, medical practitioners are able to visualize the receptor. In addition to the synthesis of PK11195, three other analogues were devised using the same methodology as for PK11195. Firstly, a Heck reaction was used to form the isoquinoline core, followed by a Suzuki reaction to couple the correct phenyl ring.
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New iodinated quinoline-2-carboxamides for SPECT imaging of the Translocator Protein
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Louise Stevenson, Adriana Tavares, Aurélie Brunet, Fiona I. Mcgonagle, Deborah Dewar, Sally L. Pimlott, Andrew SutherlandAbstract:Abstract With the aim of developing new SPECT imaging agents for the Translocator Protein (TSPO), a small library of iodinated quinoline-2-carboxamides have been prepared and tested for binding affinity with TSPO. N,N-Diethyl-3-iodomethyl-4-phenylquinoline-2-carboxamide was found to have excellent affinity (Ki 12.0 nM), comparable to that of the widely used TSPO imaging agent PK11195.
