PK-11195 is an isoquinoline carboxamide which binds selectively to the peripheral benzodiazepine receptor (PBR) (also known as the mitochondrial 18 kDa translocator protein or TSPO). It is one of the most commonly used PBR ligands due to its high affinity for the PBR in all species,[1] although it is starting to be replaced by newer and more selective ligands.[2]
Early autoradiographic studies using tritiated PK11195 ([3H]PK11195) demonstrated that in the central nervous system (CNS) of rodents, it binds primarily to the ependymal walls, choroid plexus, and olfactory bulb. However, there is a robust and widespread increase in [3H]PK11195 binding in the injured nervous system. The binding sites have since been determined to be on glial cells, including microglia, astrocytes, and infiltrating macrophages. The binding of [3H]PK11195 is considered to be a useful tool in the assessment of neuronal damage.[3][4]
In addition to being a marker of neuronal damage in animal models of CNS damage, PK11195 has been used successfully with human brain imaging techniques. (R)-[11C]PK11195 has been used in positron emission tomography (PET) scanning to visualize brain inflammation in patients with neuronal damage. Increases in (R)-[11C]PK11195 binding have been reported in patients with stroke, traumatic brain injury[5] and in patients with chronic neurodegenerative conditions including Huntington's disease and Parkinson's disease.[6][7]
The first high-resolution 3D solution structure of mammalian (mouse) translocator protein (TSPO) in a complex with its diagnostic PK11195 ligand was determined by using NMR spectroscopy techniques by scientists from the Max-Planck Institute for Biophysical Chemistry in Goettingen in Germany in March 2014[8] and has a PDB id: 2MGY. The complex stoichiometry was found to be 1 : 1 as the one consistent set of 1H ligand resonances was found with the NOE contacts to five transmembrane helices (TM) in the upper cytosolic part of the protein channel. Residues involved in the ligand binding having direct NOE contacts with the ligand were identified and are as follows A23, V26, L49, V26, A50, I52, W107, L114, A147, L150. These residues are wrapped around the PK11195 ligand forming a stable hydrophobic binding pocket that can also be regarded as the complex's hydrophobic core. The mammalian TSPO in a complex with diagnostic ligand is monomeric.
The loop located in between TM1 and TM2 helices closes the entrance to the space between helices in which are bound with PK11195 molecule. Site-directed mutagenesis studies of mTSPO revealed that region important for PK11195 binding comprise amino acids from 41 to 51, because the deletion of this region resulted in the decrease in PK11195 binding.[9]
Referencesedit
^Pike VW, Halldin C, Crouzel C, Barré L, Nutt DJ, Osman S, Shah F, Turton DR, Waters SL (May 1993). "Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites--current status". Nuclear Medicine and Biology. 20 (4): 503–25. doi:10.1016/0969-8051(93)90082-6. PMID 8389223.
^Doorduin J, de Vries EF, Dierckx RA, Klein HC (2008). "PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders". Current Pharmaceutical Design. 14 (31): 3297–315. doi:10.2174/138161208786549443. PMID 19075709.
^Cagnin A, Gerhard A, Banati RB (December 2002). "In vivo imaging of neuroinflammation". European Neuropsychopharmacology. 12 (6): 581–6. doi:10.1016/s0924-977x(02)00107-4. PMID 12468021. S2CID 35085112.
^Weissman BA, Raveh L (February 2003). "Peripheral benzodiazepine receptors: on mice and human brain imaging". Journal of Neurochemistry. 84 (3): 432–7. doi:10.1046/j.1471-4159.2003.01568.x. PMID 12558962. S2CID 38106157.
^Folkersma H, Boellaard R, Yaqub M, Kloet RW, Windhorst AD, Lammertsma AA, Vandertop WP, van Berckel BN (2011). "Widespread and prolonged increase in (R)-(11)C-PK11195 binding after traumatic brain injury". J Nucl Med. 52 (8): 1235–9. doi:10.2967/JNUMED.110.084061. PMID 21764792.
^Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P (April 2007). "Imaging microglial activation in Huntington's disease". Brain Research Bulletin. 72 (2–3): 148–51. doi:10.1016/j.brainresbull.2006.10.029. PMID 17352938. S2CID 6395304.
^Bartels AL, Leenders KL (October 2007). "Neuroinflammation in the pathophysiology of Parkinson's disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET". Movement Disorders. 22 (13): 1852–6. doi:10.1002/mds.21552. PMID 17592621.
^L. Jaremko, M. Jaremko, K. Giller, S. Becker, M. Zweckstetter, Structure of the mitochondrial translocator protein in complex with a diagnostic ligand, Science, 343 (2014) 1363-1366
^J. Fan, P. Lindemann, M.G. Feuilloley, V. Papadopoulos, Structural and functional evolution of the translocator protein (18 kDa), Curr Mol Med, 12 (2012) 369-386
April 17, 2024
11195, isoquinoline, carboxamide, which, binds, selectively, peripheral, benzodiazepine, receptor, also, known, mitochondrial, translocator, protein, tspo, most, commonly, used, ligands, high, affinity, species, although, starting, replaced, newer, more, selec. PK 11195 is an isoquinoline carboxamide which binds selectively to the peripheral benzodiazepine receptor PBR also known as the mitochondrial 18 kDa translocator protein or TSPO It is one of the most commonly used PBR ligands due to its high affinity for the PBR in all species 1 although it is starting to be replaced by newer and more selective ligands 2 PK 11195 NamesIUPAC name N Butan 2 yl 1 2 chlorophenyl N methylisoquinoline 3 carboxamideOther names PK 11195IdentifiersCAS Number 85532 75 8 Y3D model JSmol Interactive imageChEBI CHEBI 73290 NChEMBL ChEMBL15313 NChemSpider 1305 NPubChem CID 1345UNII YNF83VN1RL YCompTox Dashboard EPA DTXSID7041097InChI InChI 1S C21H21ClN2O c1 4 14 2 24 3 21 25 19 13 15 9 5 6 10 16 15 20 23 19 17 11 7 8 12 18 17 22 h5 14H 4H2 1 3H3 NKey RAVIZVQZGXBOQO UHFFFAOYSA N NSMILES CCC C N C C O c3cc1ccccc1c n3 c2ccccc2ClPropertiesChemical formula C21H21ClN2OMolar mass 352 856 g molExcept where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa N verify what is Y N Infobox references Early autoradiographic studies using tritiated PK11195 3H PK11195 demonstrated that in the central nervous system CNS of rodents it binds primarily to the ependymal walls choroid plexus and olfactory bulb However there is a robust and widespread increase in 3H PK11195 binding in the injured nervous system The binding sites have since been determined to be on glial cells including microglia astrocytes and infiltrating macrophages The binding of 3H PK11195 is considered to be a useful tool in the assessment of neuronal damage 3 4 In addition to being a marker of neuronal damage in animal models of CNS damage PK11195 has been used successfully with human brain imaging techniques R 11C PK11195 has been used in positron emission tomography PET scanning to visualize brain inflammation in patients with neuronal damage Increases in R 11C PK11195 binding have been reported in patients with stroke traumatic brain injury 5 and in patients with chronic neurodegenerative conditions including Huntington s disease and Parkinson s disease 6 7 The first high resolution 3D solution structure of mammalian mouse translocator protein TSPO in a complex with its diagnostic PK11195 ligand was determined by using NMR spectroscopy techniques by scientists from the Max Planck Institute for Biophysical Chemistry in Goettingen in Germany in March 2014 8 and has a PDB id 2MGY The complex stoichiometry was found to be 1 1 as the one consistent set of 1H ligand resonances was found with the NOE contacts to five transmembrane helices TM in the upper cytosolic part of the protein channel Residues involved in the ligand binding having direct NOE contacts with the ligand were identified and are as follows A23 V26 L49 V26 A50 I52 W107 L114 A147 L150 These residues are wrapped around the PK11195 ligand forming a stable hydrophobic binding pocket that can also be regarded as the complex s hydrophobic core The mammalian TSPO in a complex with diagnostic ligand is monomeric The loop located in between TM1 and TM2 helices closes the entrance to the space between helices in which are bound with PK11195 molecule Site directed mutagenesis studies of mTSPO revealed that region important for PK11195 binding comprise amino acids from 41 to 51 because the deletion of this region resulted in the decrease in PK11195 binding 9 References edit Pike VW Halldin C Crouzel C Barre L Nutt DJ Osman S Shah F Turton DR Waters SL May 1993 Radioligands for PET studies of central benzodiazepine receptors and PK peripheral benzodiazepine binding sites current status Nuclear Medicine and Biology 20 4 503 25 doi 10 1016 0969 8051 93 90082 6 PMID 8389223 Doorduin J de Vries EF Dierckx RA Klein HC 2008 PET imaging of the peripheral benzodiazepine receptor monitoring disease progression and therapy response in neurodegenerative disorders Current Pharmaceutical Design 14 31 3297 315 doi 10 2174 138161208786549443 PMID 19075709 Cagnin A Gerhard A Banati RB December 2002 In vivo imaging of neuroinflammation European Neuropsychopharmacology 12 6 581 6 doi 10 1016 s0924 977x 02 00107 4 PMID 12468021 S2CID 35085112 Weissman BA Raveh L February 2003 Peripheral benzodiazepine receptors on mice and human brain imaging Journal of Neurochemistry 84 3 432 7 doi 10 1046 j 1471 4159 2003 01568 x PMID 12558962 S2CID 38106157 Folkersma H Boellaard R Yaqub M Kloet RW Windhorst AD Lammertsma AA Vandertop WP van Berckel BN 2011 Widespread and prolonged increase in R 11 C PK11195 binding after traumatic brain injury J Nucl Med 52 8 1235 9 doi 10 2967 JNUMED 110 084061 PMID 21764792 Tai YF Pavese N Gerhard A Tabrizi SJ Barker RA Brooks DJ Piccini P April 2007 Imaging microglial activation in Huntington s disease Brain Research Bulletin 72 2 3 148 51 doi 10 1016 j brainresbull 2006 10 029 PMID 17352938 S2CID 6395304 Bartels AL Leenders KL October 2007 Neuroinflammation in the pathophysiology of Parkinson s disease evidence from animal models to human in vivo studies with 11C PK11195 PET Movement Disorders 22 13 1852 6 doi 10 1002 mds 21552 PMID 17592621 L Jaremko M Jaremko K Giller S Becker M Zweckstetter Structure of the mitochondrial translocator protein in complex with a diagnostic ligand Science 343 2014 1363 1366 J Fan P Lindemann M G Feuilloley V Papadopoulos Structural and functional evolution of the translocator protein 18 kDa Curr Mol Med 12 2012 369 386 Retrieved from https en wikipedia org w index php title PK 11195 amp oldid 1190748285, wikipedia, wiki, book, books, library,
