靶向巨噬细胞表面受体的PET显像剂
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摘要
炎症是机体为免于致病因素损伤而采取的防御反应,而炎症持续状态或炎症过激反应是许多疾病的病理基础.巨噬细胞作为炎症反应中主要的炎性细胞,其在炎性环境中的活化类型,对炎症的转归有很大的影响.正电子发射断层显像可利用各种正电子核素标记的分子探针,在分子层面上对巨噬细胞进行在体显像,从而对相关炎性疾病的早期诊断、预后评估、疗效判断及治疗方案的拟定等方面做出贡献.
Inflammation is a defense reaction produced by the body to protect against pathogenic factors,whereas the persistent state of inflammation or excessive inflammatory response is the pathological basis of many afflictions.As the main type of activated inflammatory cells in the inflammatory environment,macrophages exert great influence on the outcome of inflammation.For example,"M1"macrophages play a role in promoting inflammation and inhibiting cell proliferation,while"M2"macrophages have an anti-inflammatory effect,promoting cell proliferation and tissue repair.Therefore,correctly identifying macrophage subtypes can help clinical diagnosis and treatment.Positron emission tomography(PET)imaging can be used to recognize macrophages in vivo at the molecular level using various positron nuclides called markers,thereby enabling early diagnosis,prognostic evaluation,and therapeutic efficacy judgment of inflammatory diseases,as well as the development of possible treatment plans.Currently,PET imaging agents that target macrophages can be roughly classified into metabolic,enzyme,cytokine,and receptor imaging agents.However,the first three types of imaging agents have not shown good macrophage specificity and have certain limitations in distinguishing macrophage subtypes.Take metabolic imaging agents,~(18)F-FDG,as an example.Although activated macrophage cells present high uptake of~(18)F-FDG,~(18)F-FDG is still not a specific macrophages-target imaging agent,as its uptake is high in many activated immune cells and other proliferating cell resulting in high non-specific background radioactivity and dramatically lower the diagnostic accuracy.Besides,~(18)F-FDG,as a non-specific imaging agent,is oftentimes influenced by varying conditions,thereby producing false positive results when used for inflammatory cell imaging.Thus,there is a need to develop specific agents for inflammation imaging.Since macrophages have many characteristic proteins on their surface,different macrophage subtypes exhibit characteristic protein expression.Therefore,the development of radioactive molecular probes for these characteristic receptor proteins will benefit macrophage-specific imaging.Transporter-18 kD(TSPO)is currently the most widely studied macrophage-specific imaging target.However,due to the genetic polymorphism of TSPO,different TSPO PET imaging agents exhibit different TSPO binding affinities.In addition,regardless of macrophages’polarization(pro-or anti-inflammatory state),activated macrophages display similar TSPOexpression.These shortcomings limit the potential interest in TSPO.However,limitations of the TSPO have led to the identification of other molecular targets to develop new tracers of activated macrophages,and there are a lot of specific receptors have been proposed so far.Therefore,in this review,we survey alternative biological targets of recent interest in macrophage activation imaging,including purinergic receptor P_2X_7,cannabinoid receptors,chemokine receptors,folate receptorβ,mannose receptors,adenosine 2A receptor,and others,and examine the potential of these imaging molecular targets in the activation of macrophage expression.In addition,we describe promising PET imaging agents for these targets.
Inflammation is a defense reaction produced by the body to protect against pathogenic factors,whereas the persistent state of inflammation or excessive inflammatory response is the pathological basis of many afflictions.As the main type of activated inflammatory cells in the inflammatory environment,macrophages exert great influence on the outcome of inflammation.For example,"M1"macrophages play a role in promoting inflammation and inhibiting cell proliferation,while"M2"macrophages have an anti-inflammatory effect,promoting cell proliferation and tissue repair.Therefore,correctly identifying macrophage subtypes can help clinical diagnosis and treatment.Positron emission tomography(PET)imaging can be used to recognize macrophages in vivo at the molecular level using various positron nuclides called markers,thereby enabling early diagnosis,prognostic evaluation,and therapeutic efficacy judgment of inflammatory diseases,as well as the development of possible treatment plans.Currently,PET imaging agents that target macrophages can be roughly classified into metabolic,enzyme,cytokine,and receptor imaging agents.However,the first three types of imaging agents have not shown good macrophage specificity and have certain limitations in distinguishing macrophage subtypes.Take metabolic imaging agents,~(18)F-FDG,as an example.Although activated macrophage cells present high uptake of~(18)F-FDG,~(18)F-FDG is still not a specific macrophages-target imaging agent,as its uptake is high in many activated immune cells and other proliferating cell resulting in high non-specific background radioactivity and dramatically lower the diagnostic accuracy.Besides,~(18)F-FDG,as a non-specific imaging agent,is oftentimes influenced by varying conditions,thereby producing false positive results when used for inflammatory cell imaging.Thus,there is a need to develop specific agents for inflammation imaging.Since macrophages have many characteristic proteins on their surface,different macrophage subtypes exhibit characteristic protein expression.Therefore,the development of radioactive molecular probes for these characteristic receptor proteins will benefit macrophage-specific imaging.Transporter-18 kD(TSPO)is currently the most widely studied macrophage-specific imaging target.However,due to the genetic polymorphism of TSPO,different TSPO PET imaging agents exhibit different TSPO binding affinities.In addition,regardless of macrophages’polarization(pro-or anti-inflammatory state),activated macrophages display similar TSPOexpression.These shortcomings limit the potential interest in TSPO.However,limitations of the TSPO have led to the identification of other molecular targets to develop new tracers of activated macrophages,and there are a lot of specific receptors have been proposed so far.Therefore,in this review,we survey alternative biological targets of recent interest in macrophage activation imaging,including purinergic receptor P_2X_7,cannabinoid receptors,chemokine receptors,folate receptorβ,mannose receptors,adenosine 2A receptor,and others,and examine the potential of these imaging molecular targets in the activation of macrophage expression.In addition,we describe promising PET imaging agents for these targets.
引文
1 Mantovani A,Biswas S K,Galdiero M R,et al.Macrophage plasticity and polarization in tissue repair and remodelling.J Pathol,2013,229:176-185
2 De Palma M,Lewis C E.Macrophage regulation of tumor responses to anticancer therapies.Cancer Cell,2013,23:277-286
3 James M L,Belichenko N P,Shuhendler A J,et al.[18F]GE-180 PET detects reduced microglia activation after LM11A-31 therapy in a mouse model of Alzheimer’s disease.Theranostics,2017,7:1422-1436
4 Holmes S E,Hinz R,Drake R J,et al.In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia:A[11C](R)-PK11195 positron emission tomography study.Mol Psychiatry,2016,21:1672-1679
5 Schain M,Kreisl W C.Neuroinflammation in neurodegenerative disorders-A review.Curr Neurol Neurosci Rep,2017,17:25
6 Brody A L,Hubert R,Enoki R,et al.Effect of cigarette smoking on a marker for neuroinflammation:A[11C]DAA1106 positron emission tomography study.Neuropsychopharmacology,2017,42:1630-1639
7 Parente A,Feltes P K,Vallez Garcia D,et al.Pharmacokinetic analysis of11C-PBR28 in the rat model of herpes encephalitis:Comparison with(R)-11C-PK11195.J Nucl Med,2016,57:785-791
8 James M L,Fulton R R,Vercoullie J,et al.DPA-714,a new translocator protein-specific ligand:Synthesis,radiofluorination,and pharmacologic characterization.J Nucl Med,2008,49:814-822
9 Owen D R J,Gunn R N,Rabiner E A,et al.Mixed-affinity binding in humans with 18-kDa translocator protein ligands.J Nucl Med,2011,52:24-32
10 Owen D R,Howell O W,Tang S P,et al.Two binding sites for[3H]PBR28 in human brain:Implications for TSPO pet imaging of neuroinflammation.J Cereb Blood Flow Metab,2010,30:1608-1618
11 Owen D R,Yeo A J,Gunn R N,et al.An 18-kDa translocator protein(TSPO)polymorphism explains differences in binding affinity of the PETradioligand PBR28.J Cereb Blood Flow Metab,2012,32:1-5
12 Rojas C,Stathis M,Coughlin J M,et al.The low-affinity binding of second generation radiotracers targeting TSPO is associated with a unique allosteric binding site.J Neuroimmune Pharmacol,2018,13:1-5
13 Ikawa M,Lohith T G,Shrestha S,et al.11C-ER176,a radioligand for 18-kDa translocator protein,has adequate sensitivity to robustly image all three affinity genotypes in human brain.J Nucl Med,2017,58:320-325
14 Feeney C,Scott G,Raffel J,et al.Kinetic analysis of the translocator protein positron emission tomography ligand[18F]GE-180 in the human brain.Eur J Nucl Med Mol Imag,2016,43:2201-2210
15 Sridharan S,Lepelletier F X,Trigg W,et al.Comparative evaluation of three TSPO pet radiotracers in a LPS-induced model of mild neuroinflammation in rats.Mol Imag Biol,2017,19:77-89
16 Colasanti A,Guo Q,Muhlert N,et al.In vivo assessment of brain white matter inflammation in multiple sclerosis with18F-PBR111 PET.J Nucl Med,2014,55:1112-1118
17 Gulyás B,Tóth M,Schain M,et al.Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke:A PET study with the TSPO molecular imaging biomarker[11C]vinpocetine.J Neurol Sci,2012,320:110-117
18 Zinnhardt B,Pigeon H,ThézéB,et al.Combined PET imaging of the inflammatory tumor microenvironment identifies margins of unique radiotracer uptake.Cancer Res,2017,77:1831-1841
19 Gaemperli O,Shalhoub J,Owen D R J,et al.Imaging intraplaque inflammation in carotid atherosclerosis with11C-PK11195 positron emission tomography/computed tomography.Eur Heart J,2012,33:1902-1910
20 Hatori A,Yui J,Xie L,et al.Utility of translocator protein(18 kDa)as a molecular imaging biomarker to monitor the progression of liver fibrosis.Sci Rep,2015,5:17327
21 Xie L,Yui J,Hatori A,et al.Translocator protein(18kDa),a potential molecular imaging biomarker for non-invasively distinguishing nonalcoholic fatty liver disease.J Hepatol,2012,57:1076-1082
22 Bonsack F,Alleyne C H,Sukumari-Ramesh S.Augmented expression of TSPO after intracerebral hemorrhage:A role in inflammation?JNeuroinflam,2016,13:151
23 Owen D R,Narayan N,Wells L,et al.Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans.J Cereb Blood Flow Metab,2017,37:2679-2690
24 Ingwersen J,Wingerath B,Graf J,et al.Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation.J Neuroinflam,2016,13:48
25 Wang M,Gao M,Meyer J A,et al.Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PETradioligands for P2X4 receptor.BioOrg Medicinal Chem,2017,25:3835-3844
26 Rissanen E,Virta J R,Paavilainen T,et al.Adenosine A2A receptors in secondary progressive multiple sclerosis:A[11C]TMSX brain PET study.JCereb Blood Flow Metab,2013,33:1394-1401
27 Zhou X,Boellaard R,Ishiwata K,et al.In vivo evaluation of11C-preladenant for PET imaging of adenosine A2Areceptors in the conscious monkey.J Nucl Med,2017,58:762-767
28 Barret O,Hannestad J,Vala C,et al.Characterization in humans of18F-MNI-444,a PET radiotracer for brain adenosine 2A receptors.J Nucl Med,2015,56:586-591
29 Khanapur S,van Waarde A,Dierckx R A J O,et al.Preclinical evaluation and quantification of18F-fluoroethyl and18F-fluoropropyl analogs of SCH442416 as radioligands for pet imaging of the adenosine A2Areceptor in rat brain.J Nucl Med,2017,58:466-472
30 Parisi C,Napoli G,Pelegrin P,et al.M1 and M2 functional imprinting of primary microglia:Role of P2X7activation and miR-125b.Mediators Inflamm,2016,2016:2989548
31 Barberá-Cremades M,Baroja-Mazo A,Pelegrín P.Purinergic signaling during macrophage differentiation results in M2 alternative activated macrophages.J Leukocyte Biol,2016,99:289-299
32 Wu C,Zhao Y,Xiao X,et al.Graft-infiltrating macrophages adopt an M2 phenotype and are inhibited by purinergic receptor P2X7antagonist in chronic rejection.Am J TransPlant,2016,16:2563-2573
33 Lu P G,Feng H.Advances in ion channel receptor P2X7(in Chinese).Chin Neurosurg J,2008,7:373-374[卢培刚,冯华.离子通道受体P2X7的研究进展.中华神经外科疾病研究杂志,2008,7:373-374]
34 De Marchi E,Orioli E,Dal Ben D,et al.P2X7receptor as a therapeutic target.Adv Protein Chem Struct Biol,2016,104:39-79
35 Parvathenani L K,Tertyshnikova S,Greco C R,et al.P2X7mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease.J Biol Chem,2003,278:13309-13317
36 Territo P R,Meyer J A,Peters J S,et al.Characterization of11C-GSK1482160 for targeting the P2X7receptor as a biomarker for neuroinflammation.J Nucl Med,2017,58:458-465
37 Fantoni E R,Dal Ben D,Falzoni S,et al.Design,synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel18F-labelled PET tracer targeting P2X7.Ejnmmi Res,2017,7:31
38 Moore C S,Ase A R,Kinsara A,et al.P2Y12expression and function in alternatively activated human microglia.Neurol Neuroimmunol Neuroinflam,2015,2:e802
39 Armani C,Catalani E,Balbarini A,et al.Expression,pharmacology,and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages.J Leukocyte Biol,2007,81:845-855
40 Malmberg C,Ripa R S,Johnbeck C B,et al.64Cu-DOTATATE for noninvasive assessment of atherosclerosis in large arteries and its correlation with risk factors:Head-to-head comparison with68Ga-DOTATOC in 60 patients.J Nucl Med,2015,56:1895-1900
41 Tarkin J M,Joshi F R,Evans N R,et al.Detection of atherosclerotic inflammation by 68 Ga-DOTATATE PET compared to[18F]FDG PET imaging.J Am College Cardiol,2017,69:1774-1791
42 Zarruk J G,Fernández-López D,García-Yébenes I,et al.Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection.Stroke,2012,43:211-219
43 Braun M,Khan Z T,Khan M B,et al.Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.Brain Behav Immun,2017,68:224-237
44 Yu S J,Reiner D,Shen H,et al.Time-dependent protection of CB2 receptor agonist in stroke.PLoS One,2015,10:e132487
45 K?falvi A,Lemos C,Martín-Moreno A M,et al.Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer’s disease.Neuropharmacology,2016,110:519-529
46 Zhang J,Chen C.Alleviation of neuropathology by inhibition of monoacylglycerol lipase in APP transgenic mice lacking CB2 receptors.Mol Neurobiol,2017:1-9
47 Caille F,Cacheux F,Peyronneau M,et al.From structure-activity relationships on thiazole derivatives to the in vivo evaluation of a new radiotracer for cannabinoid subtype 2 PET imaging.Mol Pharmaceut,2017,14:4064-4078
48 Pottier G,Gómez-Vallejo V,Padro D,et al.PET imaging of cannabinoid type 2 receptors with[11C]A-836339 did not evidence changes following neuroinflammation in rats.J Cereb Blood Flow Metab,2017,37:1163-1178
49 Ahmad R,Postnov A,Bormans G,et al.Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease.Eur J Nucl Med Mol Imag,2016,43:2219-2227
50 Slavik R,Grether U,Müller Herde A,et al.Discovery of a high affinity and selective pyridine analog as a potential positron emission tomography imaging agent for cannabinoid type 2 receptor.J Med Chem,2015,58:4266-4277
51 Wester H J,Keller U,Schottelius M,et al.Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.Theranostics,2015,5:618-630
52 Hyafil F,Pelisek J,Laitinen I,et al.Imaging the cytokine receptor CXCR4 in atherosclerotic plaques with the radiotracer68Ga-pentixafor for PET.J Nucl Med,2017,58:499-506
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61 Mantovani A,Sozzani S,Locati M,et al.Macrophage polarization:Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.Trends Immunol,2002,23:549-555
2 De Palma M,Lewis C E.Macrophage regulation of tumor responses to anticancer therapies.Cancer Cell,2013,23:277-286
3 James M L,Belichenko N P,Shuhendler A J,et al.[18F]GE-180 PET detects reduced microglia activation after LM11A-31 therapy in a mouse model of Alzheimer’s disease.Theranostics,2017,7:1422-1436
4 Holmes S E,Hinz R,Drake R J,et al.In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia:A[11C](R)-PK11195 positron emission tomography study.Mol Psychiatry,2016,21:1672-1679
5 Schain M,Kreisl W C.Neuroinflammation in neurodegenerative disorders-A review.Curr Neurol Neurosci Rep,2017,17:25
6 Brody A L,Hubert R,Enoki R,et al.Effect of cigarette smoking on a marker for neuroinflammation:A[11C]DAA1106 positron emission tomography study.Neuropsychopharmacology,2017,42:1630-1639
7 Parente A,Feltes P K,Vallez Garcia D,et al.Pharmacokinetic analysis of11C-PBR28 in the rat model of herpes encephalitis:Comparison with(R)-11C-PK11195.J Nucl Med,2016,57:785-791
8 James M L,Fulton R R,Vercoullie J,et al.DPA-714,a new translocator protein-specific ligand:Synthesis,radiofluorination,and pharmacologic characterization.J Nucl Med,2008,49:814-822
9 Owen D R J,Gunn R N,Rabiner E A,et al.Mixed-affinity binding in humans with 18-kDa translocator protein ligands.J Nucl Med,2011,52:24-32
10 Owen D R,Howell O W,Tang S P,et al.Two binding sites for[3H]PBR28 in human brain:Implications for TSPO pet imaging of neuroinflammation.J Cereb Blood Flow Metab,2010,30:1608-1618
11 Owen D R,Yeo A J,Gunn R N,et al.An 18-kDa translocator protein(TSPO)polymorphism explains differences in binding affinity of the PETradioligand PBR28.J Cereb Blood Flow Metab,2012,32:1-5
12 Rojas C,Stathis M,Coughlin J M,et al.The low-affinity binding of second generation radiotracers targeting TSPO is associated with a unique allosteric binding site.J Neuroimmune Pharmacol,2018,13:1-5
13 Ikawa M,Lohith T G,Shrestha S,et al.11C-ER176,a radioligand for 18-kDa translocator protein,has adequate sensitivity to robustly image all three affinity genotypes in human brain.J Nucl Med,2017,58:320-325
14 Feeney C,Scott G,Raffel J,et al.Kinetic analysis of the translocator protein positron emission tomography ligand[18F]GE-180 in the human brain.Eur J Nucl Med Mol Imag,2016,43:2201-2210
15 Sridharan S,Lepelletier F X,Trigg W,et al.Comparative evaluation of three TSPO pet radiotracers in a LPS-induced model of mild neuroinflammation in rats.Mol Imag Biol,2017,19:77-89
16 Colasanti A,Guo Q,Muhlert N,et al.In vivo assessment of brain white matter inflammation in multiple sclerosis with18F-PBR111 PET.J Nucl Med,2014,55:1112-1118
17 Gulyás B,Tóth M,Schain M,et al.Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke:A PET study with the TSPO molecular imaging biomarker[11C]vinpocetine.J Neurol Sci,2012,320:110-117
18 Zinnhardt B,Pigeon H,ThézéB,et al.Combined PET imaging of the inflammatory tumor microenvironment identifies margins of unique radiotracer uptake.Cancer Res,2017,77:1831-1841
19 Gaemperli O,Shalhoub J,Owen D R J,et al.Imaging intraplaque inflammation in carotid atherosclerosis with11C-PK11195 positron emission tomography/computed tomography.Eur Heart J,2012,33:1902-1910
20 Hatori A,Yui J,Xie L,et al.Utility of translocator protein(18 kDa)as a molecular imaging biomarker to monitor the progression of liver fibrosis.Sci Rep,2015,5:17327
21 Xie L,Yui J,Hatori A,et al.Translocator protein(18kDa),a potential molecular imaging biomarker for non-invasively distinguishing nonalcoholic fatty liver disease.J Hepatol,2012,57:1076-1082
22 Bonsack F,Alleyne C H,Sukumari-Ramesh S.Augmented expression of TSPO after intracerebral hemorrhage:A role in inflammation?JNeuroinflam,2016,13:151
23 Owen D R,Narayan N,Wells L,et al.Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans.J Cereb Blood Flow Metab,2017,37:2679-2690
24 Ingwersen J,Wingerath B,Graf J,et al.Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation.J Neuroinflam,2016,13:48
25 Wang M,Gao M,Meyer J A,et al.Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PETradioligands for P2X4 receptor.BioOrg Medicinal Chem,2017,25:3835-3844
26 Rissanen E,Virta J R,Paavilainen T,et al.Adenosine A2A receptors in secondary progressive multiple sclerosis:A[11C]TMSX brain PET study.JCereb Blood Flow Metab,2013,33:1394-1401
27 Zhou X,Boellaard R,Ishiwata K,et al.In vivo evaluation of11C-preladenant for PET imaging of adenosine A2Areceptors in the conscious monkey.J Nucl Med,2017,58:762-767
28 Barret O,Hannestad J,Vala C,et al.Characterization in humans of18F-MNI-444,a PET radiotracer for brain adenosine 2A receptors.J Nucl Med,2015,56:586-591
29 Khanapur S,van Waarde A,Dierckx R A J O,et al.Preclinical evaluation and quantification of18F-fluoroethyl and18F-fluoropropyl analogs of SCH442416 as radioligands for pet imaging of the adenosine A2Areceptor in rat brain.J Nucl Med,2017,58:466-472
30 Parisi C,Napoli G,Pelegrin P,et al.M1 and M2 functional imprinting of primary microglia:Role of P2X7activation and miR-125b.Mediators Inflamm,2016,2016:2989548
31 Barberá-Cremades M,Baroja-Mazo A,Pelegrín P.Purinergic signaling during macrophage differentiation results in M2 alternative activated macrophages.J Leukocyte Biol,2016,99:289-299
32 Wu C,Zhao Y,Xiao X,et al.Graft-infiltrating macrophages adopt an M2 phenotype and are inhibited by purinergic receptor P2X7antagonist in chronic rejection.Am J TransPlant,2016,16:2563-2573
33 Lu P G,Feng H.Advances in ion channel receptor P2X7(in Chinese).Chin Neurosurg J,2008,7:373-374[卢培刚,冯华.离子通道受体P2X7的研究进展.中华神经外科疾病研究杂志,2008,7:373-374]
34 De Marchi E,Orioli E,Dal Ben D,et al.P2X7receptor as a therapeutic target.Adv Protein Chem Struct Biol,2016,104:39-79
35 Parvathenani L K,Tertyshnikova S,Greco C R,et al.P2X7mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease.J Biol Chem,2003,278:13309-13317
36 Territo P R,Meyer J A,Peters J S,et al.Characterization of11C-GSK1482160 for targeting the P2X7receptor as a biomarker for neuroinflammation.J Nucl Med,2017,58:458-465
37 Fantoni E R,Dal Ben D,Falzoni S,et al.Design,synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel18F-labelled PET tracer targeting P2X7.Ejnmmi Res,2017,7:31
38 Moore C S,Ase A R,Kinsara A,et al.P2Y12expression and function in alternatively activated human microglia.Neurol Neuroimmunol Neuroinflam,2015,2:e802
39 Armani C,Catalani E,Balbarini A,et al.Expression,pharmacology,and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages.J Leukocyte Biol,2007,81:845-855
40 Malmberg C,Ripa R S,Johnbeck C B,et al.64Cu-DOTATATE for noninvasive assessment of atherosclerosis in large arteries and its correlation with risk factors:Head-to-head comparison with68Ga-DOTATOC in 60 patients.J Nucl Med,2015,56:1895-1900
41 Tarkin J M,Joshi F R,Evans N R,et al.Detection of atherosclerotic inflammation by 68 Ga-DOTATATE PET compared to[18F]FDG PET imaging.J Am College Cardiol,2017,69:1774-1791
42 Zarruk J G,Fernández-López D,García-Yébenes I,et al.Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection.Stroke,2012,43:211-219
43 Braun M,Khan Z T,Khan M B,et al.Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.Brain Behav Immun,2017,68:224-237
44 Yu S J,Reiner D,Shen H,et al.Time-dependent protection of CB2 receptor agonist in stroke.PLoS One,2015,10:e132487
45 K?falvi A,Lemos C,Martín-Moreno A M,et al.Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer’s disease.Neuropharmacology,2016,110:519-529
46 Zhang J,Chen C.Alleviation of neuropathology by inhibition of monoacylglycerol lipase in APP transgenic mice lacking CB2 receptors.Mol Neurobiol,2017:1-9
47 Caille F,Cacheux F,Peyronneau M,et al.From structure-activity relationships on thiazole derivatives to the in vivo evaluation of a new radiotracer for cannabinoid subtype 2 PET imaging.Mol Pharmaceut,2017,14:4064-4078
48 Pottier G,Gómez-Vallejo V,Padro D,et al.PET imaging of cannabinoid type 2 receptors with[11C]A-836339 did not evidence changes following neuroinflammation in rats.J Cereb Blood Flow Metab,2017,37:1163-1178
49 Ahmad R,Postnov A,Bormans G,et al.Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease.Eur J Nucl Med Mol Imag,2016,43:2219-2227
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