Injury to the central nervous system is characterized by localization of activated microglia at the site of injury. The peripheral benzodiazepine receptor expressed on the outer mitochondrial membrane of the activated microglia is a sensitive biomarker for the detection of this neuroinflammatory response to an insult. PK11195, an isoquinoline ligand that specifically binds peripheral benzodiazepine receptor, can be tagged with a positron emitter and used as a tracer for molecular imaging of this receptor in vivo by positron emission tomography (PET). [11C](R)PK11195 has been used in the imaging of various neuroinflammatory disorders, such as Alzheimer disease and multiple sclerosis. On the basis of our small-animal PET imaging studies using a neonatal rabbit model of maternal inflammation-induced cerebral palsy, we propose that PET imaging using [11C](R)PK11195 may be a valuable tool for detecting neuroinflammation in the brain of newborns born to mothers with chorioamnionitis.
Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TBChorioamnionitis and cerebral palsy in term and near-term infants. JAMA. 2003;290(20):2677-2684.
2.
Bell MJ, Hallenbeck JMEffects of intrauterine inflammation on developing rat brain. J Neurosci Res. 2002;70(4):570-579.
3.
Cai Z., Pan ZL, Pang Y., Evans OB, Rhodes PGCytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res. 2000;47(1):64-72.
4.
Saadani-Makki F., Kannan S., Lu X., et al. Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy. Am J Obstet Gynecol. 2008 ;199(6):651-657.
5.
Espey MG, Chernyshev ON, Reinhard JF Jr, Namboodiri MA, Colton CAActivated human microglia produce the excitotoxin quinolinic acid. Neuroreport. 1997;8(2):431-434.
6.
Li J., Baud O., Vartanian T., Volpe JJ, Rosenberg PAPeroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci U S A. 2005;102(28):9936-9941.
7.
Block ML, Zecca L., Hong JSMicroglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57-69.
8.
Lawson LJ, Perry VH, Dri P., Gordon S.Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39(1):151-170.
9.
Vilhardt F.Microglia: phagocyte and glia cell. Int J Biochem Cell Biol . 2005;37(1):17-21.
10.
Nimmerjahn A., Kirchhoff F., Helmchen F.Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314-1318.
11.
Billiards SS , Haynes RL, Folkerth RD, et al. Development of microglia in the cerebral white matter of the human fetus and infant. J Comp Neurol . 2006;497(2):199-208.
12.
Dheen ST, Kaur C., Ling EAMicroglial activation and its implications in the brain diseases. Curr Med Chem. 2007;14(11):1189-1197.
13.
Pekny M., Nilsson M.Astrocyte activation and reactive gliosis. Glia. 2005;50(4):427-434.
14.
Lossinsky AS , Shivers RRStructural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions . Review. Histol Histopathol. 2004;19(2):535-564.
15.
O’Callaghan JP, Sriram K., Miller DBDefining ‘‘neuroinflammation.’’ . Ann N Y Acad Sci.2008;1139:318-330.
16.
Gray E., Thomas TL, Betmouni S., Scolding N., Love S.Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol. 2008;18(1):86-95.
17.
Mosley RL, Benner EJ, Kadiu I., et al. Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res. 2006;6(5):261-281.
18.
Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RBNeuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res. 2008;39(1):1-16.
19.
Crocker SJ, Whitmire JK, Frausto RF, et al. Persistent macrophage/microglial activation and myelin disruption after experimental autoimmune encephalomyelitis in tissue inhibitor of metalloproteinase-1-deficient mice. Am J Pathol. 2006;169(6): 2104-2116.
20.
Bolmont T., Haiss F., Eicke D., et al. Dynamics of the microglial/ amyloid interaction indicate a role in plaque maintenance. J Neurosci. 2008;28(16):4283-4292.
21.
Hickman SE, Allison EK, El Khoury J.Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. Neuroscience. 2008;28(33):8354-8360.
22.
Fahn S., Przedborski S.Parkinsonism. In Merritts neurology. In: Rowland LP, ed. New York, NY: Lippincott; 2000:679-693.
Francalanci P., Eymard-Pierre E., Dionisi-Vici C., et al. Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27. Neurology. 2001;57(2):265-270.
25.
Vargas DL, Nascimbene C., Krishnan C., Zimmerman AW, Pardo CANeuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67-81.
26.
Banati RB, Goerres GW, Myers R., et al. [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology . 1999;53(9): 2199-2203.
27.
Kumar A., Chugani HT, Luat A., Asano E., Sood S.Epilepsy surgery in a case of encephalitis: use of 11C-PK11195 positron emission tomography. Pediatr Neurol. 2008;38(6):439-442.
28.
Taniwaki Y. , Kato M., Araki T., Kobayashi T.Microglial activation by epileptic activities through the propagation pathway of kainic acid-induced hippocampal seizures in the rat. Neurosci Lett. 1996;217(1):29-32.
29.
Borda JT, Alvarez X., Mohan M., et al. Clinical and immunopathologic alterations in rhesus macaques affected with globoid cell leukodystrophy. Am J Pathol. 2008;172(1):98-111.
30.
McGuinness MC, Powers JM, Bias WB, et al. Human leukocyte antigens and cytokine expression in cerebral inflammatory demyelinative lesions of X-linked adrenoleukodystrophy and multiple sclerosis. J Neuroimmunol. 1997 ;75(1-2):174-182.
31.
Dammann O., Leviton A.Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Semin Pediatr Neurol. 1998;5(3):190-201.
32.
O’Shea TM, Kothadia JM, Roberts DD, Dillard RGPerinatal events and the risk of intraparenchymal echodensity in very-low-birthweight neonates. Paediatr Perinat Epidemiol. 1998; 12(4):408-421.
33.
Bejar RF, Vaucher YE, Benirschke K., Berry CCPostnatal white matter necrosis in preterm infants. J Perinatol . 1992;12(1):3-8.
34.
Haynes RL, Folkerth RD, Keefe RJ, et al. Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J Neuropathol Exp Neurol . 2003;62(5): 441-450.
35.
Volpe JJNeurobiology of periventricular leukomalacia in the premature infant. Pediatr Res. 2001;50(5):553-562.
36.
Volpe JJCerebral white matter injury of the premature infant-more common than you think. Pediatrics. 2003;112(1 pt 1):176-180.
37.
Martinez E. , Figueroa R., Garry D., et al. Elevated amniotic fluid interleukin-6 as a predictor of neonatal periventricular leukomalacia and intraventricular hemorrhage. J Matern Fetal Investig. 1998;8(3):101-107.
38.
Yoon BH, Romero R., Park JS, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol . 2000;182(3):675-681.
39.
Lonergan M. , Aponso D., Marvin KW, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptors, and the soluble receptor osteoprotegerin in human gestational membranes and amniotic fluid during pregnancy and labor at term and preterm. J Clin Endocrinol Metab. 2003; 88(8):3835-3844.
40.
Nelson KB, Dambrosia JM, Grether JK, Phillips TMNeonatal cytokines and coagulation factors in children with cerebral palsy . Ann Neurol. 1998;44(4):665-675.
41.
du Plessis AJ, Volpe JJPerinatal brain injury in the preterm and term newborn. Curr Opin Neurol. 2002;15(2):151-157.
42.
Hailer NP, Vogt C., Korf HW, Dehghani F.Interleukin-1beta exacerbates and interleukin-1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures. Eur J Neurosci. 2005;21(9):2347-2360.
43.
Lehnardt S. , Lachance C., Patrizi S., et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci. 2002;22(7):2478-2486.
44.
Dommergues MA, Plaisant F., Verney C., Gressens P.Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection. Neuroscience. 2003;121(3):619-628.
45.
Hagberg H., Peebles D., Mallard C.Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev. 2002;8(1):30-38.
46.
Gurley C., Nichols J., Liu S., Phulwani NK, Esen N., Kielian T.Microglia and astrocyte activation by toll-like receptor ligands: modulation by PPAR-gamma agonists. PPAR Res. 2008; 2008:453120.
47.
Fern R., Moller T.Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J Neurosci. 2000;20(1):34-42.
48.
Salter MG, Fern R.NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature. 2005;438(7071):1167-1171.
49.
Garnier M., Boujrad N., Ogwuegbu SO, Hudson JR Jr, Papadopoulos V.The polypeptide diazepam-binding inhibitor and a higher affinity mitochondrial peripheral-type benzodiazepine receptor sustain constitutive steroidogenesis in the R2C Leydig tumor cell line. J Biol Chem. 1994;269(35):22105-22112.
50.
Braestrup C. , Squires RFSpecific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci U S A. 1977;74(9):3805-3809.
51.
Gavish M., Bachman I., Shoukrun R., et al. Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev. 1999; 51(4):629-650.
52.
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;27(8): 402-409.
53.
Papadopoulos V., Widmaier EP, Amri H., et al. In vivo studies on the role of the peripheral benzodiazepine receptor (PBR) in steroidogenesis. Endocr Res. 1998;24(3-4):479-487.
54.
Casellas P. , Galiegue S., Basile ASPeripheral benzodiazepine receptors and mitochondrial function. Neurochem Int. 2002; 40(6):475-486.
55.
Banati RBVisualising microglial activation in vivo. Glia. 2002;40(2):206-217.
56.
Gerhard A., Banati RB, Goerres GB, et al. [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology. 2003;61(5):686-689.
57.
McEnery MW, Snowman AM, Trifiletti RR, Snyder SHIsolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A. 1992; 89(8):3170-3174.
Wang JK, Morgan JI, Spector S.Benzodiazepines that bind at peripheral sites inhibit cell proliferation. Proc Natl Acad Sci U S A.1984;81(3):753-756.
60.
Lenfant M., Haumont J., Zavala F.In vivo immunomodulating activity of PK 1195, a structurally unrelated ligand for ‘‘peripheral’’ benzodiazepine binding sites-I. Potentiation in mice of the humoral response to sheep red blood cells. Int J Immunopharmacol. 1986;8(7):825-828.
61.
Ruff MR, Pert CB, Weber RJ, Wahl LM, Wahl SM, Paul SMBenzodiazepine receptor-mediated chemotaxis of human monocytes. Science. 1985;229(4719):1281-1283.
62.
Banati RB, Newcombe J., Gunn RN, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000;123(pt 11):2321-2337.
63.
Chen MK, Guilarte TRImaging the peripheral benzodiazepine receptor response in central nervous system demyelination and remyelination. Toxicol Sci. 2006;91(2):532-539.
64.
Chen MK, Baidoo K., Verina T., Guilarte TRPeripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain . 2004;127(pt 6):1379-1392.
65.
Kuhlmann AC, Guilarte TRCellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J Neurochem. 2000;74(4):1694-1704.
66.
Chen MK, Guilarte TRTranslocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair . Pharmacol Ther. 2008;118(1):1-17.
67.
James ML, Selleri S., Kassiou M.Development of ligands for the peripheral benzodiazepine receptor. Curr Med Chem. 2006;13(17):1991-2001.
68.
Papadopoulos V., Amri H., Boujrad N., et al. Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis. Steroids. 1997;62(1):21-28.
69.
Gerhard A., Trender-Gerhard I., Turkheimer F., Quinn NP, Bhatia KP, Brooks DJIn vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord. 2006;21(1):89-93.
70.
Black KL, Ikezaki K., Santori E., Becker DP, Vinters HVSpecific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumors in rat and man. Cancer. 1990 ; 65(1):93-97.
71.
Okello A., Edison P., Archer HA, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology. 2009;72(1):56-62.
72.
Edison P., Archer HA, Gerhard A., et al. Microglia, amyloid, and cognition in Alzheimer’s disease: an [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis . 2008;32(3):412-419.
73.
Cagnin A., Brooks DJ, Kennedy AM, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358(9280): 461-467.
74.
van Berckel BN, Bossong MG, Boellaard R., et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)[11C]PK11195 positron emission tomography study. Biol Psychiatry. 2008;64(9):820-822.
75.
Vas A., Shchukin Y., Karrenbauer VD, et al. Functional neuroimaging in multiple sclerosis with radiolabelled glia markers: preliminary comparative PET studies with [11C]vinpocetine and [11C]PK11195 in patients. J Neurol Sci. 2008 ;264(1-2):9-17.
76.
Tai YF, Pavese N., Gerhard A., et al. Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain. 2007;130(pt 7):1759-1766.
77.
Pavese N., Gerhard A., Tai YF, et al. Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology. 2006;66(11):1638-1643.
78.
Messmer K., Reynolds GPIncreased peripheral benzodiazepine binding sites in the brain of patients with Huntington’s disease. Neurosci Lett. 1998;241(1):53-56.
79.
Gerhard A., Pavese N., Hotton G., et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis . 2006;21(2): 404-412.
80.
Ouchi Y., Yoshikawa E., Sekine Y., et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol. 2005;57(2):168-175.
81.
Henkel K., Karitzky J., Schmid M., et al. Imaging of activated microglia with PET and [11C]PK 11195 in corticobasal degeneration. Mov Disord. 2004 ;19(7):817-821.
82.
Gerhard A., Watts J., Trender-Gerhard I., et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration. Mov Disord. 2004;19(10):1221-1226.
83.
Turner MR, Cagnin A., Turkheimer FE, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study . Neurobiol Dis. 2004;15(3):601-609.
84.
Gerhard A., Neumaier B., Elitok E., et al. In vivo imaging of activated microglia using [11C]PK11195 and positron emission tomography in patients after ischemic stroke. Neuroreport. 2000;11(13):2957-2960.
85.
Ramsay SC, Weiller C., Myers R., et al. Monitoring by PET of macrophage accumulation in brain after ischaemic stroke. Lancet. 1992;339(8800):1054-1055.
86.
Pappata S., Levasseur M., Gunn RN, et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK1195. Neurology. 2000 ;55(7):1052-1054.
87.
Shah F., Hume SP, Pike VW, Ashworth S., McDermott J.Synthesis of the enantiomers of [N-methyl-11C]PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats. Nucl Med Biol. 1994;21(4):573-581.
88.
Kannan S., Saadani-Makki F., Muzik O., et al. Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with 11C-(R)-PK11195 and small-animal PET. J Nucl Med. 2007;48(6):946-954.
89.
Myers R., Manjil LG, Cullen BM, Price GW, Frackowiak RS, Cremer JEMacrophage and astrocyte populations in relation to [3H]PK 11195 binding in rat cerebral cortex following a local ischaemic lesion. J Cereb Blood Flow Metab. 1991;11(2):314-322.
90.
Venneti S., Wagner AK, Wang G., et al. The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging. Exp Neurol. 2007;207(1):118-127.
91.
Dumont F., De VF, Versijpt J., et al. In vivo evaluation in mice and metabolism in blood of human volunteers of [123I]iodo-PK11195: a possible single-photon emission tomography tracer for visualization of inflammation. Eur J Nucl Med. 1999;26(3):194-200.
92.
Lammertsma AA, Hume SPSimplified reference tissue model for PET receptor studies. Neuroimage. 1996;4(3 pt 1):153-158.
93.
Boutin H., Chauveau F., Thominiaux C., et al. 11C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J Nucl Med . 2007;48(4):573-581.
94.
Monier A., Adle-Biassette H., Delezoide AL, Evrard P., Gressens P., Verney C.Entry and distribution of microglial cells in human embryonic and fetal cerebral cortex. J Neuropathol Exp Neurol. 2007;66(5):372-382.
95.
Chugani DC, Kedersha NL, Rome LHVault immunofluoresence in the brain: new insights regarding the origin of microglia. J Neurosci. 1991;11(1):256-268.
96.
Brenner DJ, Hall EJComputed tomography-an increasing source of radiation exposure. N Engl J Med. 2007;357(22): 2277-2284.
