The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic cells.Brain TSPO expression is relativel...The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic cells.Brain TSPO expression is relatively low under physiological conditions,but is upregulated in response to glial cell activation.As the primary index of neuroinflammation,TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases,including Alzheimer’s disease(AD),amyotrophic lateral sclerosis(ALS),Parkinson’s disease(PD),multiple sclerosis(MS),major depressive disorder(MDD)and obsessive compulsive disorder(OCD).In this context,numerous TSPO-targeted positron emission tomography(PET)tracers have been developed.Among them,several radioligands have advanced to clinical research studies.In this review,we will overview the recent development of TSPO PET tracers,focusing on the radioligand design,radioisotope labeling,pharmacokinetics,and PET imaging evaluation.Additionally,we will consider current limitations,as well as translational potential for future application of TSPO radiopharmaceuticals.This review aims to not only present the challenges in current TSPO PET imaging,but to also provide a new perspective on TSPO targeted PET tracer discovery efforts.Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.展开更多
Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite t...Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.展开更多
In this article, an effective feasible method to synthesize translocator protein 18kDa （TSPO） imidazopyridine ligand 7 is discussed. A new procedure for the synthesis of the key intermediate 17 has been developed in...In this article, an effective feasible method to synthesize translocator protein 18kDa （TSPO） imidazopyridine ligand 7 is discussed. A new procedure for the synthesis of the key intermediate 17 has been developed in four steps （condensation, diazo reaction, hydrolysis, amidation） from 2-aminopyridine 18. The overall yield was increased from 18% to 31.6%. One of the key steps is using activated copper powder as a catalyst in several cycles. Finally, reduction of 17 with Zn dust completed the synthesis of TSPO imidazopyridine ligand 7 in 86% yield.展开更多
The present study explored the 18-kDa translocator protein radioligand ^(18)F-PBR06 as a PET imaging biomarker for diagnosis of inflammation and compared it with ^(18)F-FDG for differentiation of inflammation and lung...The present study explored the 18-kDa translocator protein radioligand ^(18)F-PBR06 as a PET imaging biomarker for diagnosis of inflammation and compared it with ^(18)F-FDG for differentiation of inflammation and lung tumors in animals.^(18)F-PBR06 was synthesized with an average decay-corrected radiochemical yield of 30–40%(end of synthesis, EOS), and the radiochemical purity was greater than 99%. The inflammation-to-blood ratio of ^(18)FPBR06(3.53 ± 0.26) was higher than the tumor-to-blood ratio(1.77 ± 0.35)(P \ 0.001). The inflammation-tomuscle ratio of ^(18)F-PBR06(2.33 ± 0.64) was also higher than the tumor-to-muscle ratio(1.45 ± 0.14)(P = 0.036).Micro-PET/CT images showed high uptake of ^(18)F-FDG in both inflamed muscles and lung tumor tissues. However,^(18)F-PBR06 uptake in inflamed muscles remained higher than that in the lung tumor tissues, following 90 min of dynamic Micro-PET/CT imaging. Further, macrophages in the inflammatory regions showed a higher fluorescence signal than in lung tumor tissues. Results of the study confirmed that ^(18)F-PBR06 PET/CT imaging allowed for diagnosis of inflammation. Moreover,^(18)F-PBR06 uptake in the inflammatory regions was significantly higher than in lung tumor tissues, suggesting that ^(18)F-PBR06 PET/CT imaging has potential to differentiate between peripheral lung cancer and inflammation nodules.展开更多
Electromagnetic fields (EMFs) can interact with biological tissues exerting positive as well as negative effects on cell viability, but the underlying sensing and signaling mechanisms are largely unknown. So far in ex...Electromagnetic fields (EMFs) can interact with biological tissues exerting positive as well as negative effects on cell viability, but the underlying sensing and signaling mechanisms are largely unknown. So far in excitable cells EMF exposure was postulated to cause Ca<sup>2+</sup> influx through voltage-dependent Ca channels (VDCC) leading to cell activation and an antioxidant response. Upon further activation oxidative stress causing DNA damage or cell death may follow. Here we report collected evidence from literature that voltage dependent anion channels (VDAC) located not only in the outer microsomal membrane but also in the cytoplasmic membrane convert to Ca<sup><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;">2+</span></sup> conducting channels of varying capacities upon subtle changes of the applied EMF even in non-excitable cells like erythrocytes. Thus, VDAC can be targeted by external EMF in both types of membranes to release Ca<sup><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;"><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;">2+</sup></span><span style="white-space:normal;"></span> into the cytosol. The role of frequency, pulse modulation or polarization remains to be investigated in suitable cellular models. VDACs are associated with several other proteins, among which the 18 kDa translocator (TSPO) is of specific interest since it was characterized as the central benzodiazepine receptor in neurons. Exhibiting structural similarities with magnetoreceptors we propose that TSPO could sense the magnetic component of the EMF and thus together with VDAC could trigger physiological as well as pathological cellular responses. Pulsed EMFs in the frequency range of the brain-wave communication network may explain psychic disturbances of electromagnetic hypersensitive persons. An important support is provided from human psychology that states defi展开更多
The emission tomographic imaging of activated microglia in the brain moves into the focus of neuroscientific research with increasing recognition of contributions of early inflammatory processes to neurodegenerative, ...The emission tomographic imaging of activated microglia in the brain moves into the focus of neuroscientific research with increasing recognition of contributions of early inflammatory processes to neurodegenerative, traumatic, cancerous and infectious diseases of the brain. Whereas the mitochondrial isoform of the 18 kDa translocator protein (TSPO1) has been the main cellular target for positron emission tomography (PET) of this type of cells for decades, alternative marker proteins in the plasma membrane of microglia challenge efforts in ligand development, recently. The present report includes PET approaches using the chemokine receptor CX3CR1 and the FR2 folate receptor in parallel to small molecule PET tracers available for in vivo visualization of the “classical” target TSPO1. It compares first and second generation of TSPO1 ligands as well as new compounds like the tetrahydrocarbazole [18F]GE-180 and the quinazoline [11C]ER176 presumed to reduce polymorphism-related inter-subject variations, with allosteric ligands for the chemokine receptor CX3CR1 and with radio labelled folate conjugates targeting the folate “cargo” receptor FR1 and the FR2 receptor characteristic for anti-inflammatory M2 microglia.展开更多
基金support of K.C.Wong Education Foundation(China)the Project of Innovative Team for the Guangdong Universities(2018KCXTD001,China)+1 种基金financially supported by the National Natural Science Foundation of China(Nos.81701751 and 81871383)Guangdong Basic and Applied Basic Research Foundation(2020A1515011192,China)
文摘The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic cells.Brain TSPO expression is relatively low under physiological conditions,but is upregulated in response to glial cell activation.As the primary index of neuroinflammation,TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases,including Alzheimer’s disease(AD),amyotrophic lateral sclerosis(ALS),Parkinson’s disease(PD),multiple sclerosis(MS),major depressive disorder(MDD)and obsessive compulsive disorder(OCD).In this context,numerous TSPO-targeted positron emission tomography(PET)tracers have been developed.Among them,several radioligands have advanced to clinical research studies.In this review,we will overview the recent development of TSPO PET tracers,focusing on the radioligand design,radioisotope labeling,pharmacokinetics,and PET imaging evaluation.Additionally,we will consider current limitations,as well as translational potential for future application of TSPO radiopharmaceuticals.This review aims to not only present the challenges in current TSPO PET imaging,but to also provide a new perspective on TSPO targeted PET tracer discovery efforts.Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
文摘Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.
基金Supported by the National Natural Science Foundation of China(81373254,81373254,81071182)the Applied Basic Research Program of Wuhan Municipal Bureau of Science and Technology(2013020501010176)+3 种基金the Scientific and Technological Innovative Research Team of Wuhan(2013070204020048)Academic Award for Excellent Ph.D. Candidates Funded by Ministry of Education of China(5052012306001)Innovation Seed Fund of Wuhan University School of Medicine,the Fundamental Research Funds for the Central Universities(2012306020201)Medical Innovation Foundation of Fujian Province,China(2009-CXB-46)
文摘In this article, an effective feasible method to synthesize translocator protein 18kDa （TSPO） imidazopyridine ligand 7 is discussed. A new procedure for the synthesis of the key intermediate 17 has been developed in four steps （condensation, diazo reaction, hydrolysis, amidation） from 2-aminopyridine 18. The overall yield was increased from 18% to 31.6%. One of the key steps is using activated copper powder as a catalyst in several cycles. Finally, reduction of 17 with Zn dust completed the synthesis of TSPO imidazopyridine ligand 7 in 86% yield.
基金funded in part by the National Natural Science Foundation of China(Nos.11875114,81471706,and 81871407)Science and Technology Commission of Shanghai Municipality(No.16410722700)sponsored by the Shanghai Sailing Program(No.17YF1417400)
文摘The present study explored the 18-kDa translocator protein radioligand ^(18)F-PBR06 as a PET imaging biomarker for diagnosis of inflammation and compared it with ^(18)F-FDG for differentiation of inflammation and lung tumors in animals.^(18)F-PBR06 was synthesized with an average decay-corrected radiochemical yield of 30–40%(end of synthesis, EOS), and the radiochemical purity was greater than 99%. The inflammation-to-blood ratio of ^(18)FPBR06(3.53 ± 0.26) was higher than the tumor-to-blood ratio(1.77 ± 0.35)(P \ 0.001). The inflammation-tomuscle ratio of ^(18)F-PBR06(2.33 ± 0.64) was also higher than the tumor-to-muscle ratio(1.45 ± 0.14)(P = 0.036).Micro-PET/CT images showed high uptake of ^(18)F-FDG in both inflamed muscles and lung tumor tissues. However,^(18)F-PBR06 uptake in inflamed muscles remained higher than that in the lung tumor tissues, following 90 min of dynamic Micro-PET/CT imaging. Further, macrophages in the inflammatory regions showed a higher fluorescence signal than in lung tumor tissues. Results of the study confirmed that ^(18)F-PBR06 PET/CT imaging allowed for diagnosis of inflammation. Moreover,^(18)F-PBR06 uptake in the inflammatory regions was significantly higher than in lung tumor tissues, suggesting that ^(18)F-PBR06 PET/CT imaging has potential to differentiate between peripheral lung cancer and inflammation nodules.
基金supported by the National Natural Science Foundation of China(81925012,92049301,and 82050008)the Innovation Program of Shanghai Municipal Education Commission(2021-01-07-00-07.E00074)+3 种基金the New Cornerstone Science Foundation(NCI202242)the Shanghai Municipal Science and Technology(20JC1410900,major project(2018SHZDZX01)and ZJLab)the Science and Technology Commission of Shanghai Municipality(22S11900100)the fellowship of China Postdoctoral Science Foundation(2021M690686)。
文摘Electromagnetic fields (EMFs) can interact with biological tissues exerting positive as well as negative effects on cell viability, but the underlying sensing and signaling mechanisms are largely unknown. So far in excitable cells EMF exposure was postulated to cause Ca<sup>2+</sup> influx through voltage-dependent Ca channels (VDCC) leading to cell activation and an antioxidant response. Upon further activation oxidative stress causing DNA damage or cell death may follow. Here we report collected evidence from literature that voltage dependent anion channels (VDAC) located not only in the outer microsomal membrane but also in the cytoplasmic membrane convert to Ca<sup><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;">2+</span></sup> conducting channels of varying capacities upon subtle changes of the applied EMF even in non-excitable cells like erythrocytes. Thus, VDAC can be targeted by external EMF in both types of membranes to release Ca<sup><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;"><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;"><sup></sup></span><span style="white-space:normal;">2+</sup></span><span style="white-space:normal;"></span> into the cytosol. The role of frequency, pulse modulation or polarization remains to be investigated in suitable cellular models. VDACs are associated with several other proteins, among which the 18 kDa translocator (TSPO) is of specific interest since it was characterized as the central benzodiazepine receptor in neurons. Exhibiting structural similarities with magnetoreceptors we propose that TSPO could sense the magnetic component of the EMF and thus together with VDAC could trigger physiological as well as pathological cellular responses. Pulsed EMFs in the frequency range of the brain-wave communication network may explain psychic disturbances of electromagnetic hypersensitive persons. An important support is provided from human psychology that states defi
文摘The emission tomographic imaging of activated microglia in the brain moves into the focus of neuroscientific research with increasing recognition of contributions of early inflammatory processes to neurodegenerative, traumatic, cancerous and infectious diseases of the brain. Whereas the mitochondrial isoform of the 18 kDa translocator protein (TSPO1) has been the main cellular target for positron emission tomography (PET) of this type of cells for decades, alternative marker proteins in the plasma membrane of microglia challenge efforts in ligand development, recently. The present report includes PET approaches using the chemokine receptor CX3CR1 and the FR2 folate receptor in parallel to small molecule PET tracers available for in vivo visualization of the “classical” target TSPO1. It compares first and second generation of TSPO1 ligands as well as new compounds like the tetrahydrocarbazole [18F]GE-180 and the quinazoline [11C]ER176 presumed to reduce polymorphism-related inter-subject variations, with allosteric ligands for the chemokine receptor CX3CR1 and with radio labelled folate conjugates targeting the folate “cargo” receptor FR1 and the FR2 receptor characteristic for anti-inflammatory M2 microglia.
