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Review

Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010–2015; part 1)

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Pages 1325-1351 | Received 29 Mar 2016, Accepted 26 Aug 2016, Published online: 13 Sep 2016

References

  • Snyder SH, Verma A, Trifiletti RR. The peripheral-type benzodiazepine receptor: a protein of mitochondrial outer membranes utilizing porphyrins as endogenous ligands. Faseb J. 1987 Oct;1(4):282–288.
  • Papadopoulos V, Baraldi M, Guilarte TR, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006 Aug;27(8):402–409.
  • Braestrup C, Albrechtsen R, Squires RF. High-densities of benzodiazepine receptors in human cortical areas. Nature. 1977;269(5630):702–704.
  • Braestrup C, Squires RF. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci U S A. 1977;74(9):3805–3809.
  • Hauet T, Yao Z-X, Bose HS, et al. Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into Leydig cell mitochondria. Mol Endocrinol. 2005 Feb;19(2):540–554.
  • Veenman L, Gavish M. The role of 18 kDa mitochondrial translocator protein (TSPO) in programmed cell death, and effects of steroids on TSPO expression. Curr Mol Med. 2012 May;12(4):398–412.
  • Gavish M, Bachman I, Shoukrun R, et al. Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev. 1999 Dec;51(4):629–650.
  • Larcher JC, Vayssiere JL, Lemarquer FJ, et al. Effects of peripheral benzodiazepines upon the O2 consumption of neuro-blastoma cells. Eur J Pharmacol. 1989 Feb 28;161(2–3):197–202.
  • Krestinina OV, Grachev DE, Odinokova IV, et al. Effect of peripheral benzodiazepine receptor (PBR/TSPO) ligands on opening of Ca2+-induced pore and phosphorylation of 3.5-kDa polypeptide in rat brain mitochondria. Biochemistry-Moscow+. 2009 Apr;74(4):421–429.
  • Banati RB, Middleton RJ, Chan R, et al. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun. 2014;5:5452.
  • Schüle C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol. 2014 Feb;113:79–87.
  • Wolf L, Bauer A, Melchner D, et al. Enhancing neurosteroid synthesis–relationship to the pharmacology of translocator protein (18 kDa) (TSPO) ligands and benzodiazepines. Pharmacopsychiatry. 2015 Mar;48(2):72–77.
  • Tu LN, Morohaku K, Manna PR, et al. Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis. J Biol Chem. 2014 Oct 3;289(40):27444–27454.
  • Fan J, Campioli E, Midzak A, et al. Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7261–7266.
  • McEnery MW. The mitochondrial benzodiazepine receptor: evidence for association with the voltage-dependent anion channel (VDAC). J Bioenerg Biomembr. 1992 Feb;24(1):63–69.
  • Cho JH, Park JH, Chung CG, et al. Parkin-mediated responses against infection and wound involve TSPO-VDAC complex in Drosophila. Biochem Biophys Res Commun. 2015 Jul 17–24;463(1–2):1–6.
  • Vianello A, Casolo V, Petrussa E, et al. The mitochondrial permeability transition pore (PTP) - an example of multiple molecular exaptation? Biochim Biophys Acta. 2012 Nov;1817(11):2072–2086.
  • Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol. 2009 Jun;46(6):821–831.
  • Šileikytė J, Blachly-Dyson E, Sewell R, et al. Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (translocator protein of 18 kDa (TSPO)). J Biol Chem. 2014 May 16;289(20):13769–13781.
  • Batarseh A, Papadopoulos V. Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol. 2010 Oct 7;327(1–2):1–12.
  • Veenman L, Papadopoulos V, Gavish M. Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response. Curr Pharm Des. 2007;13(23):2385–2405.
  • Veenman L, Shandalov Y, Gavish M. VDAC activation by the 18 kDa translocator protein (TSPO), implications for apoptosis. J Bioenerg Biomembr. 2008 Jun;40(3):199–205.
  • Karlstetter M, Nothdurfter C, Aslanidis A, et al. Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation. 2014;11:3.
  • Chua SW, Kassiou M, Ittner LM. The translocator protein as a drug target in Alzheimer’s disease. Expert Rev Neurother. 2014 Apr;14(4):439–448.
  • Veenman L, Vainshtein A, Gavish M. TSPO as a target for treatments of diseases, including neuropathological disorders. Cell Death Dis. 2015;6:e1911.
  • Veiga S, Azcoitia I, Garcia-Segura LM. Extragonadal synthesis of estradiol is protective against kainic acid excitotoxic damage to the hippocampus. Neuroreport. 2005 Sep 28;16(14):1599–1603.
  • Rupprecht R, Papadopoulos V, Rammes G, et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010 Dec;9(12):971–988.
  • Jaremko L, Jaremko M, Giller K, et al. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science. 2014 Mar 21;343(6177):1363–1366.
  • Jaremko Ł, Jaremko M, Giller K, et al. Conformational flexibility in the transmembrane protein TSPO. Chemistry. 2015 Nov 9;21(46):16555–16563.
  • Li F, Liu J, Zheng Y, et al. Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism. Science. 2015 Jan 30;347(6221):555–558.
  • Korkhov VM, Sachse C, Short JM, et al. Three-dimensional structure of TspO by electron cryomicroscopy of helical crystals. Structure. 2010 Jun 9;18(6):677–687.
  • Guo YZ, Kalathur RC, Liu Q, et al. Protein structure. Structure and activity of tryptophan-rich TSPO proteins. Science. 2015 Jan 30;347(6221):551–555.
  • Li H, Papadopoulos V. Peripheral-type benzodiazepine receptor function in cholesterol transport. Identification of a putative cholesterol recognition/interaction amino acid sequence and consensus pattern. Endocrinology. 1998 Dec;139(12):4991–4997.
  • Doorduin J, de Vries EFJ, Dierckx RA, et al. PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des. 2008;14(31):3297–3315.
  • Pike VW, Halldin C, Crouzel C, et al. Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites–current status. Nucl Med Biol. 1993 May;20(4):503–525.
  • Cagnin A, Gerhard A, Banati RB. The concept of in vivo imaging of neuroinflammation with [11C](R)-PK11195 PET. Ernst Schering Res Found Workshop. 2002;39:179–191.
  • Bartels AL, Leenders KL. Neuroinflammation in the pathophysiology of Parkinson’s disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET. Mov Disord. 2007 Oct 15;22(13):1852–1856.
  • Belloli S, Moresco RM, Matarrese M, et al. Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration. Neurochem Int. 2004 May;44(6):433–440.
  • Leonelli E, Yague JG, Ballabio M, et al. Ro5-4864, a synthetic ligand of peripheral benzodiazepine receptor, reduces aging-associated myelin degeneration in the sciatic nerve of male rats. Mech Ageing Dev. 2005 Nov;126(11):1159–1163.
  • Barron AM, Garcia-Segura LM, Caruso D, et al. Ligand for translocator protein reverses pathology in a mouse model of Alzheimer’s disease. J Neurosci. 2013 May 15;33(20):8891–8897.
  • Kita A, Kohayakawa H, Kinoshita T, et al. Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand. Br J Pharmacol. 2004 Aug;142(7):1059–1072.
  • Da Settimo F, Simorini F, Taliani S, et al. Anxiolytic-like effects of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis. J Med Chem. 2008 Sep 25;51(18):5798–5806.
  • Rupprecht R, Rammes G, Eser D, et al. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science. 2009 Jul 24;325(5939):490–493.
  • Miyoshi M, Ito H, Arakawa R, et al. Quantitative analysis of peripheral benzodiazepine receptor in the human brain using PET with (11)C-AC-5216. J Nucl Med. 2009 Jul;50(7):1095–1101.
  • Zivkovic B, Morel E, Joly D, et al. Pharmacological and behavioral profile of alpidem as an anxiolytic. Pharmacopsychiatry. 1990 May;23:108–113.
  • Frattola L, Garreau M, Piolti R, et al. Comparison of the efficacy, safety and withdrawal of alpidem and alprazolam in anxious patients. Brit J Psychiat. 1994 Jul;165:94–100.
  • Berson A, Descatoire V, Sutton A, et al. Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. J Pharmacol Exp Ther. 2001 Nov;299(2):793–800.
  • Romeo E, Auta J, Kozikowski AP, et al. 2-Aryl-3-indoleacetamides (Fgin-1) - a new class of potent and specific ligands for the mitochondrial Dbi receptor (Mdr). J Pharmacol Exp Ther. 1992 Sep;262(3):971–978.
  • Romeo E, Cavallaro S, Korneyev A, et al. Stimulation of brain steroidogenesis by 2-aryl-indole-3-acetamide derivatives acting at the mitochondrial diazepam-binding inhibitor receptor complex. J Pharmacol Exp Ther. 1993 Oct;267(1):462–471.
  • Ferzaz B, Brault E, Bourliaud G, et al. SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1 -acetamide), a peripheral benzodiazepine receptor ligand, promotes neuronal survival and repair. J Pharmacol Exp Ther. 2002 Jun;301(3):1067–1078.
  • Chauveau F, Boutin H, Van Camp N, et al. In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa). Eur J Nucl Med Mol Imaging. 2011 Mar;38(3):509–514.
  • Moon BS, Kim BS, Park C, et al. [F-18]fluoromethyl-PBR28 as a potential radiotracer for TSPO: preclinical comparison with [C-11]PBR28 in a rat model of neuroinflammation. Bioconjugate Chem. 2014 Feb;25(2):442–450.
  • Venneti S, Wang G, Wiley CA. The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds to activated and infected brain macrophages in areas of synaptic degeneration: implications for PET imaging of neuroinflammation in lentiviral encephalitis. Neurobiol Dis. 2008 Feb;29(2):232–241.
  • Bordet T, Buisson B, Michaud M, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007 Aug;322(2):709–720.
  • Li YQ, Zhang YY, Han WW, et al. TRO19622 promotes myelin repair in a rat model of demyelination. Int J Neurosci. 2013 Nov;123(11):810–822.
  • Zanetta C, Nizzardo M, Simone C, et al. Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials. Clin Ther. 2014 Jan;36(1):128–140.
  • Murail S, Robert JC, Coic YM, et al. Secondary and tertiary structures of the transmembrane domains of the translocator protein TSPO determined by NMR. Stabilization of the TSPO tertiary fold upon ligand binding. Biochim Biophys Acta. 2008 Jun;1778(6):1375–1381.
  • Farges R, Joseph-Liauzun E, Shire D, et al. Site-directed mutagenesis of the peripheral benzodiazepine receptor: identification of amino acids implicated in the binding site of Ro5-4864. Mol Pharmacol. 1994 Dec;46(6):1160–1167.
  • Ortore G, Tuccinardi T, Martinelli A. Computational studies on translocator protein (TSPO) and its ligands. Curr Top Med Chem. 2012;12(4):352–359.
  • Li F, Xia Y, Meiler J, et al. Characterization and modeling of the oligomeric state and ligand binding behavior of purified translocator protein 18 kDa from Rhodobacter sphaeroides. Biochemistry-Us. 2013 Aug 27;52(34):5884–5899.
  • Midzak AS, Akula N, Lecanu L, et al. Identification of novel ligands targeted to the cholesterol recognition/interaction amino acid consensus (CRAC) domain of the translocator protein (TSPO). Endocr Rev. 2010 Jun;31(3):S2494–S94.
  • Li F, Liu J, Garavito RM, et al. Evolving understanding of translocator protein 18 kDa (TSPO). Pharmacol Res. 2015 Sep;99:404–409.
  • Rone MB, Midzak AS, Issop L, et al. Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones. Mol Endocrinol. 2012 Nov;26(11):1868–1882.
  • Owen DRJ, Gunn RN, Rabiner EA, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med. 2011 Jan;52(1):24–32.
  • Li F, Liu J, Liu N, et al. Translocator protein 18 kDa (TSPO): an old protein with new functions? Biochemistry. 2016 May 9;55(20):2821–2831.
  • Wang J. Comment on “Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism”. Science. 2015 Oct 30;350(6260):519.
  • Li F, Liu J, Zheng Y, et al. Response to comment on “Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism”. Science. 2015 Oct 30;350(6260):519.
  • Imamoto N, Momosaki S, Fujita M, et al. [11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats. NeuroImage. 2013 Oct 1;79:121–128.
  • Gee KW Use of peripheral-type benzodiazepine sites for treatment of CNS trauma or disease. WO1993011771 A1. 1993.
  • Hirvonen J, Roivainen A, Virta J, et al. Human biodistribution and radiation dosimetry of 11C-(R)-PK11195, the prototypic PET ligand to image inflammation. Eur J Nucl Med Mol Imaging. 2010 Mar;37(3):606–612.
  • Pajouhesh H, Lenz GR. Medicinal chemical properties of successful central nervous system drugs. NeuroRx. 2005 Oct;2(4):541–553.
  • Matarrese M, Moresco RM, Cappelli A, et al. Labeling and evaluation of N-[11C]methylated quinoline-2-carboxamides as potential radioligands for visualization of peripheral benzodiazepine receptors. J Med Chem. 2001 Feb 15;44(4):579–585.
  • Cappelli A, Pericot Mohr G, Gallelli A, et al. Structure-activity relationships in carboxamide derivatives based on the targeted delivery of radionuclides and boron atoms by means of peripheral benzodiazepine receptor ligands. J Med Chem. 2003 Aug 14;46(17):3568–3571.
  • Cappelli A, Matarrese M, Moresco RM, et al. Synthesis, labeling, and biological evaluation of halogenated 2-quinolinecarboxamides as potential radioligands for the visualization of peripheral benzodiazepine receptors. Bioorg Med Chem. 2006 Jun 15;14(12):4055–4066.
  • Yu W, Wang E, Voll RJ, et al. Synthesis, fluorine-18 radiolabeling, and in vitro characterization of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinoline carboxamide derivatives as potential PET radioligands for imaging peripheral benzodiazepine receptor. Bioorg Med Chem. 2008 Jun 1;16(11):6145–6155.
  • Goodman MM, Patterson RE, Alexander RW, et al. Haloisoquinoline carboxamide. US5998624 A. 1999
  • Han Z, Slack RS, Li W, et al. Expression of peripheral benzodiazepine receptor (PBR) in human tumors: relationship to breast, colorectal, and prostate tumor progression. J Recept Signal Transduct Res. 2003;23(2–3):225–238.
  • Chen Y, Sajjad M, Wang Y, et al. TSPO 18 kDa (PBR) targeted photosensitizers for cancer imaging (PET) and PDT. ACS Med Chem Lett. 2011 Feb 10;2(2):136–141.
  • Castellano S, Taliani S, Viviano M, et al. Structure-activity relationship refinement and further assessment of 4-phenylquinazoline-2-carboxamide translocator protein ligands as antiproliferative agents in human glioblastoma tumors. J Med Chem. 2014 Mar 27;57(6):2413–2428.
  • Castellano S, Taliani S, Milite C, et al. Synthesis and biological evaluation of 4-phenylquinazoline-2-carboxamides designed as a novel class of potent ligands of the translocator protein. J Med Chem. 2012 May 10;55(9):4506–4510.
  • Castellano S, Da SPF, Martini C, et al. Translocator protein imaging agents; methods of manufacture, and methods of use thereof. WO2014164678 A1. 2014.
  • Mokrov GV, Deeva OA, Gudasheva TA, et al. Design, synthesis and anxiolytic-like activity of 1-arylpyrrolo[1,2-a]pyrazine-3-carboxamides. Bioorg Med Chem. 2015 Jul 1;23(13):3368–3378.
  • Pellow S, Chopin P, File SE, et al. Validation of open: closedarm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985 Aug;14(3):149–167.
  • Gavish M, Veenman JA, Shterenberg A, et al. Heterocyclic derivatives, pharmaceutical compositions and methods of use thereof. US 8541428 B2. 2013.
  • Gavish M, Veenman JA, Shterenberg A, et al. Quinazoline scaffold based compounds, pharmaceutical compositions and methods of use thereof. WO 2015162615 A1. 2015.
  • Okuyama S, Chaki S, Yoshikawa R, et al. Neuropharmacological profile of peripheral benzodiazepine receptor agonists, DAA1097 and DAA1106. Life Sci. 1999;64(16):1455–1464.
  • Chaki S, Harada K, Nagamine M, et al. Aryloxyaniline derivatives. WO 1999006353 A1. 1999.
  • Okubo T, Yoshikawa R, Chaki S, et al. Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands. Bioorg Med Chem. 2004 Jan 15;12(2):423–438.
  • Langstrom B, Rahman O, Bergstrom M, et al. Carbon-isotope monoxide labeling of daa1106 and its analogues to be used as tracers for a peripheral type benzodiazepine binding site. WO2007036785 A2. 2007.
  • Taliani S, Pugliesi I, Da Settimo F. Structural requirements to obtain highly potent and selective 18 kDa translocator protein (TSPO) ligands. Curr Top Med Chem. 2011;11(7):860–886.
  • Briard E, Zoghbi SS, Imaizumi M, et al. Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo. J Med Chem. 2008 Jan 10;51(1):17–30.
  • Buck JR, McKinley ET, Hight MR, et al. Quantitative, preclinical PET of translocator protein expression in glioma using F-18-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline. J Nucl Med. 2011 Jan 1;52(1):107–114.
  • Wang M, Gao MZ, Miller KD, et al. Synthesis of [C-11]PBR06 and [F-18]PBR06 as agents for positron emission tomographic (PET) imaging of the translocator protein (TSPO). Steroids. 2011 Nov;76(12):1331–1340.
  • Zhang MR, Maeda J, Furutsuka K, et al. [18F]FMDAA1106 and [18F]FEDAA1106: two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR). Bioorg Med Chem Lett. 2003 Jan 20;13(2):201–204.
  • Takano A, Piehl F, Hillert J, et al. In vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106. EJNMMI Res. 2013;3(1):30.
  • Varrone A, Mattsson P, Forsberg A, et al. In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients. Eur J Nucl Med Mol Imaging. 2013 Jun;40(6):921–931.
  • Park E, Gallezot J-D, Delgadillo A, et al. (11)C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas. Eur J Nucl Med Mol Imaging. 2015 Jun;42(7):1081–1092.
  • Wadsworth HJ, Trigg WJ Aryloxyanilide derivatives. WO2010106166 A2. 2010.
  • Lee BC, Moon BS, Jung JH [18f]fluoromethyl group-introduced radiotracer for positron emission tomography for targeting brain neuroinflammation, synthesis thereof, and method for evaluating biological results using same. WO2015037774 A1. 2015.
  • Wilson AA, Garcia A, Parkes J, et al. Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors. Nucl Med Biol. 2008 Apr;35(3):305–314.
  • Suridjan I, Rusjan PM, Voineskos AN, et al. Neuroinflammation in healthy aging: a PET study using a novel translocator protein 18kDa (TSPO) radioligand, [(18)F]-FEPPA. NeuroImage. 2014 Jan 1;84:868–875.
  • Suridjan I, Rusjan PM, Kenk M, et al. Quantitative imaging of neuroinflammation in human white matter: a positron emission tomography study with translocator protein 18 kDa radioligand, [18F]-FEPPA. Synapse. 2014 Nov;68(11):536–547.
  • Suridjan I, Pollock BG, Verhoeff NP, et al. In-vivo imaging of grey and white matter neuroinflammation in Alzheimer’s disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA. Mol Psychiatry. 2015 Feb 24;20(12):1579–1587.
  • Mabrouk R, Rusjan PM, Mizrahi R, et al. Image derived input function for [18F]-FEPPA: application to quantify translocator protein (18 kDa) in the human brain. PLoS One. 2014;9(12):e115768.
  • Kenk M, Selvanathan T, Rao N, et al. Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA. Schizophr Bull. 2015 Jan;41(1):85–93.
  • Lehmann L, Thiele A, Heinrich T, et al. Daa-pyridine as peripheral benzodiazepine receptor ligand for diagnostic imaging and pharmaceutical treatment. WO2010015340 A1. 2010.
  • Wadsworth HJ, Shea DO Aryloxyanilide imaging agents. US20120244073 A1. 2012.
  • Veiga S, Azcoitia I, Garcia-Segura LM. Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity. J Neurosci Res. 2005 Apr 1;80(1):129–137.
  • Soustiel JF, Zaaroor M, Vlodavsky E, et al. Neuroprotective effect of Ro5-4864 following brain injury. Exp Neurol. 2008 Dec;214(2):201–208.
  • Gavish M, Veenman JA, Shterenberg A, et al. Heterocyclic derivatives, pharmaceutical compositions and methods of use thereof. US20100029658 A1. 2010.
  • Campiani G, Nacci V, Fiorini I, et al. Synthesis, biological activity, and SARs of pyrrolobenzoxazepine derivatives, a new class of specific “peripheral-type” benzodiazepine receptor ligands. J Med Chem. 1996 Aug 30;39(18):3435–3450.
  • Campiani G, Ramunno A, Fiorini I, et al. Synthesis of new molecular probes for investigation of steroid biosynthesis induced by selective interaction with peripheral type benzodiazepine receptors (PBR). J Med Chem. 2002 Sep 12;45(19):4276–4281.
  • Arstad E, Robins EG, Zhao Y Tricyclic oxazepines as in vivo imaging compounds. US20090317328 A1. 2009.
  • Campiani G, Nacci V, Williams DC, et al. Apoptosis-inducing compounds. WO1999056736 A2. 1999.
  • Rizzetto E, Castellano S, Florio C, et al. 5-aryl-imidazo[2,1-c][1,4]benzodiazepine derivatives as tricyclic constrained analogues of diazepam and Ro5-4864. Synthesis and binding properties at peripheral and central benzodiazepine receptors. Die Pharmazie. 2006 Jun;61(6):505–510.
  • Anzini M, Cappelli A, Vomero S, et al. Molecular basis of peripheral vs central benzodiazepine receptor selectivity in a new class of peripheral benzodiazepine receptor ligands related to alpidem. J Med Chem. 1996 Oct 11;39(21):4275–4284.
  • Midzak A, Denora N, Laquintana V, et al. 2-Phenylimidazo[1,2-a]pyridine-containing ligands of the 18-kDa translocator protein (TSPO) behave as agonists and antagonists of steroidogenesis in a mouse leydig tumor cell line. Eur J Pharm Sci. 2015 Aug 30;76:231–237.
  • Denora N, Laquintana V, Pisu MG, et al. 2-Phenyl-imidazo[1,2-a]pyridine compounds containing hydrophilic groups as potent and selective ligands for peripheral benzodiazepine receptors: synthesis, binding affinity and electrophysiological studies. J Med Chem. 2008 Nov 13;51(21):6876–6888.
  • Denora N, Cassano T, Laquintana V, et al. Novel codrugs with GABAergic activity for dopamine delivery in the brain. Int J Pharm. 2012 Nov 1;437(1–2):221–231.
  • Perrone M, Moon BS, Park HS, et al. A novel PET imaging probe for the detection and monitoring of translocator protein 18 kDa expression in pathological disorders. Sci Rep. 2016;6:20422.
  • Cappelli A, Giuliani G, Valenti S, et al. Synthesis and structure-activity relationship studies in peripheral benzodiazepine receptor ligands related to alpidem. Bioorg Med Chem. 2008 Mar 15;16(6):3428–3437.
  • Cappelli A, Bini G, Valenti S, et al. Synthesis and structure-activity relationship studies in translocator protein ligands based on a pyrazolo[3,4-b]quinoline scaffold. J Med Chem. 2011 Oct 27;54(20):7165–7175.
  • Middleton R, Banati R, Liu GJ Transgenic non-human organisms with non-functional tspo genes. WO2014138791 A1. 2014.
  • Yang R, Li Y, Li Y, et al. 2-Aryl imidazo[1,2-a]pyridine-3-acetamide derivatives, preparation methods and uses thereof. US20130203754 A1. 2013.
  • Selleri S, Bruni F, Costagli C, et al. 2-Arylpyrazolo[1,5-a]pyrimidin-3-yl acetamides. New potent and selective peripheral benzodiazepine receptor ligands. Bioorg Med Chem. 2001 Oct;9(10):2661–2671.
  • James ML, Fulton RR, Vercoullie J, et al. DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med. 2008 May;49(5):814–822.
  • Kassiou M, James ML 2-arylpyrazolo[l,5-alpha]pyrimidin-3-yl acetamide derivatives as ligands for translocator protein (18 kda). US20120189548 A1. 2012.
  • Vicidomini C, Panico M, Greco A, et al. In vivo imaging and characterization of [(18)F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET. Nucl Med Biol. 2015 Mar;42(3):309–316.
  • Médran-Navarrete V, Damont A, Peyronneau M-A, et al. Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18kDa with PET. Bioorg Med Chem Lett. 2014 Mar 15;24(6):1550–1556.
  • Lavisse S, Inoue K, Jan C, et al. [18F]DPA-714 PET imaging of translocator protein TSPO (18 kDa) in the normal and excitotoxically-lesioned nonhuman primate brain. Eur J Nucl Med Mol Imaging. 2015 Mar;42(3):478–494.
  • Tang D, McKinley ET, Hight MR, et al. Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: discovery of a novel TSPO PET ligand for cancer imaging. J Med Chem. 2013 Apr 25;56(8):3429–3433.
  • Banister SD, Beinat C, Wilkinson SM, et al. Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO). Eur J Med Chem. 2015 Mar 26;93:392–400.
  • Damont A, Médran-Navarrete V, Cacheux F, et al. Novel pyrazolo[1,5-a]pyrimidines as translocator protein 18 kDa (TSPO) ligands: synthesis, in vitro biological evaluation, [(18)F]-labeling, and in vivo neuroinflammation PET images. J Med Chem. 2015 Sep 24;58(18):7449–7464.
  • Pomper MG, Wang H, Guilarte TR Tspo-targeting compounds and uses thereof. US20110212025 A1. 2011.
  • Chamoles NA, Blanco M, Gaggioli D, et al. Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards. Clin Chim Acta. 2002 Apr;318(1–2):133–137.
  • Kassiou M, Reynolds A Novel compounds and their uses in diagnosis. US20110142757 A1. 2011.
  • Kassiou M, James ML, Luus CA Translocator protein ligands. US20110044898 A1. 2011.
  • Murata T, Masumoto K, Kondo K, et al. 2-aryl-8-oxodihydropurine derivative, process for the producing the same, medicinal compositions containing the same, and intermediates thereof. US6372740 B1. 2002.
  • Wang D-S, Tian Z, Guo -Y-Y, et al. Anxiolytic-like effects of translocator protein (TSPO) ligand ZBD-2 in an animal model of chronic pain. Mol Pain. 2015;11:16.
  • Owen D, Wilkins M Methods to predict binding affinity of tspo imaging agents to tspo. US20140301947 A1. 2014.
  • Fukaya T, Kodo T, Ishiyama T, et al. Design, synthesis and structure-activity relationships of novel benzoxazolone derivatives as 18 kDa translocator protein (TSPO) ligands. Bioorg Med Chem. 2012 Sep 15;20(18):5568–5582.
  • Fukaya T, Ishiyama T, Baba S, et al. Identification of a novel benzoxazolone derivative as a selective, orally active 18 kDa translocator protein (TSPO) ligand. J Med Chem. 2013 Oct 24;56(20):8191–8195.
  • Fukaya T, Kodo T, Ishiyama T, et al. Design, synthesis and structure-activity relationship of novel tricyclic benzimidazolone derivatives as potent 18 kDa translocator protein (TSPO) ligands. Bioorg Med Chem. 2013 Mar 1;21(5):1257–1267.
  • Tiwari AK, Yui J, Fujinaga M, et al. Characterization of a novel acetamidobenzoxazolone-based PET ligand for translocator protein (18 kDa) imaging of neuroinflammation in the brain. J Neurochem. 2014 May;129(4):712–720.
  • Tiwari AK, Fujinaga M, Yui J, et al. Synthesis and evaluation of new (18)F-labelled acetamidobenzoxazolone-based radioligands for imaging of the translocator protein (18 kDa, TSPO) in the brain. Org Biomol Chem. 2014 Dec 21;12(47):9621–9630.
  • Tiwari AK, Ji B, Yui J, et al. [18F]FEBMP: positron emission tomography imaging of TSPO in a model of neuroinflammation in rats, and in vitro autoradiograms of the human brain. Theranostics. 2015;5(9):961–969.
  • Fujibayashi N, Fukaya T, Kodo T, et al. Novel heterocyclic compound. WO2005080334 A1. 2005.
  • Veenman L, Vainshtein A, Yasin N, et al. Tetrapyrroles as endogenous TSPO ligands in eukaryotes and prokaryotes: comparisons with synthetic ligands. Int J Mol Sci. 2016;17(6):880.
  • Seneviratne MS, Faccenda D, De Biase V, et al. PK11195 inhibits mitophagy targeting the F1Fo-ATPsynthase in Bcl-2 knock-down cells. Curr Mol Med. 2012 May;12(4):476–482.
  • Hatty CR, Banati RB. Protein-ligand and membrane-ligand interactions in pharmacology: the case of the translocator protein (TSPO). Pharmacol Res. 2015 Oct;100:58–63.

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