Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers
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Abstract
Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [11C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [11C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents.
Keywords
Neuroinflammation PET [11C]PK11195 Peripheral benzodiazepine receptor (PBR) Translocator protein 18kDa (TSPO)Notes
Acknowledgements
We wish to thank all our excellent colleagues with whom we had exciting discussions during the TOPIM’07 “Imaging neuroinflammation” meeting in Les Houches (February 2007) and the 5th French Australian symposium on Nuclear medicine (November 2007), with a special emphasis for our continuous dialogue with Pr. Michael Kassiou and the many fruitful discussions with Prs. Andrew Katsifis and Denis Guilloteau. Work in our laboratory is funded by the EMIL and DIMI European networks of excellence. NVC is the recipient of a FWO fellowship from Belgium.
References
- 1.Schmid-Schonbein GW. Analysis of inflammation. Annu Rev Biomed Eng. 2006;8:93–131.PubMedCrossRefGoogle Scholar
- 2.Bailey SL, Carpentier PA, McMahon EJ, Begolka WS, Miller SD. Innate and adaptive immune responses of the central nervous system. Crit Rev Immunol. 2006;26(2):149–88.PubMedGoogle Scholar
- 3.Dirnagl U. Inflammation in stroke: the good, the bad, and the unknown. Ernst Schering Res Found Workshop 2004;(47):87–99.Google Scholar
- 4.Chavarria A, Alcocer-Varela J. Is damage in central nervous system due to inflammation? Autoimmun Rev. 2004;3(4):251–60.PubMedCrossRefGoogle Scholar
- 5.Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12(9):1005–15.PubMedGoogle Scholar
- 6.Ladeby R, Wirenfeldt M, Garcia-Ovejero D, Fenger C, Dissing-Olesen L, Dalmau I, et al. Microglial cell population dynamics in the injured adult central nervous system. Brain Res Brain Res Rev. 2005;48(2):196–206.PubMedCrossRefGoogle Scholar
- 7.Benavides J, Fage D, Carter C, Scatton B. Peripheral type benzodiazepine binding sites are a sensitive indirect index of neuronal damage. Brain Res. 1987;421(1–2):167–72.PubMedCrossRefGoogle Scholar
- 8.Weissman BA, Raveh L. Peripheral benzodiazepine receptors: on mice and human brain imaging. J Neurochem. 2003;84(3):432–7.PubMedCrossRefGoogle Scholar
- 9.Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27(8):402–9.PubMedCrossRefGoogle Scholar
- 10.Turton DR, Pike VW, Cartoon M, Widdowson DA. Preparation of a Potential Marker for Glial Cells -(N-Methyl-C-11)Ro5–4864. J Labelled Compd Rad. 1984;21(11–1):1209–10.Google Scholar
- 11.Camsonne R, Crouzel C, Comar D, Maziere M, Prenant C, Sastre J, et al. Synthesis of N-(C-11) methyl, N-(methyl-1 propyl), (chloro-2 phenyl)-1 isoquinoleine carboxamide-3 (PK11195)-a new ligand for peripheral benzodiazepine receptors. J Labelled Compd Rad. 1984;21(10):985–91.CrossRefGoogle Scholar
- 12.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):179–91.Google Scholar
- 13.Banati RB. Visualising microglial activation in vivo. Glia. 2002;40(2):206–17.PubMedCrossRefGoogle Scholar
- 14.de Vries EF, Vroegh J, Dijkstra G, Moshage H, Elsinga PH, Jansen PL, et al. Synthesis and evaluation of a fluorine-18 labeled antisense oligonucleotide as a potential PET tracer for iNOS mRNA expression. Nucl Med Biol. 2004;31(5):605–12.PubMedCrossRefGoogle Scholar
- 15.Pomper MG, Musachio JL, Scheffel U, Macdonald JE, McCarthy DJ, Reif DW, et al. Radiolabeled neuronal nitric oxide synthase inhibitors: synthesis, in vivo evaluation, and primate PET studies. J Nucl Med. 2000;41(8):1417–25.PubMedGoogle Scholar
- 16.Zhang J, McCarthy TJ, Moore WM, Currie MG, Welch MJ. Synthesis and evaluation of two positron-labeled nitric oxide synthase inhibitors, S-[11C]methylisothiourea and S-(2-[18F]fluoroethyl)isothiourea, as potential positron emission tomography tracers. J Med Chem. 1996;39(26):5110–8.PubMedCrossRefGoogle Scholar
- 17.Zhang J, Xu M, Dence CS, Sherman EL, McCarthy TJ, Welch MJ. Synthesis, in vivo evaluation and PET study of a carbon-11-labeled neuronal nitric oxide synthase (nNOS) inhibitor S-methyl-l-thiocitrulline. J Nucl Med. 1997;38(8):1273–8.PubMedGoogle Scholar
- 18.Wust FR, Hohne A, Metz P. Synthesis of 18F-labelled cyclooxygenase-2 (COX-2) inhibitors via Stille reaction with 4-[18F]fluoroiodobenzene as radiotracers for positron emission tomography (PET). Org Biomol Chem. 2005;3(3):503–7.PubMedCrossRefGoogle Scholar
- 19.de Vries EF, van Waarde A, Buursma AR, Vaalburg W. Synthesis and in vivo evaluation of 18F-desbromo-DuP-697 as a PET tracer for cyclooxygenase-2 expression. J Nucl Med. 2003;44(10):1700–6.PubMedGoogle Scholar
- 20.Majo VJ, Prabhakaran J, Simpson NR, Van Heertum RL, Mann JJ, Kumar JS. A general method for the synthesis of aryl [11C]methylsulfones: potential PET probes for imaging cyclooxygenase-2 expression. Bioorg Med Chem Lett. 2005;15(19):4268–71.PubMedCrossRefGoogle Scholar
- 21.McCarthy TJ, Sheriff AU, Graneto MJ, Talley JJ, Welch MJ. Radiosynthesis, in vitro validation, and in vivo evaluation of 18F-labeled COX-1 and COX-2 inhibitors. J Nucl Med. 2002;43(1):117–24.PubMedGoogle Scholar
- 22.Prabhakaran J, Underwood MD, Parsey RV, Arango V, Majo VJ, Simpson NR, et al. Synthesis and in vivo evaluation of [18F]-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul fonamide as a PET imaging probe for COX-2 expression. Bioorg Med Chem. 2007;15(4):1802–7.PubMedCrossRefGoogle Scholar
- 23.Stevens H, Van de Wiele C, Santens P, Jansen HM, De Reuck J, Dierckx R, et al. Cobalt-57 and technetium-99 m-HMPAO-labeled leukocytes for visualization of ischemic infarcts. J Nucl Med. 1998;39(3):495–8.PubMedGoogle Scholar
- 24.Stevens H, Jansen HM, De Reuck J, Lemmerling M, Strijckmans K, Goethals P, et al. 55-Cobalt (Co) as a PET-tracer in stroke, compared with blood flow, oxygen metabolism, blood volume and gadolinium-MRI. J Neurol Sci. 1999;171(1):11–8.PubMedCrossRefGoogle Scholar
- 25.De Reuck J, Stevens H, Jansen H, Keppens J, Strijckmans K, Goethals P, et al. The significance of cobalt-55 positron emission tomography in ischemic stroke. Journal of Stroke and Cerebrovascular Diseases. 1999;8(1):17–21.PubMedCrossRefGoogle Scholar
- 26.De Reuck J, Santens P, Strijckmans K, Lemahieu I. Cobalt-55 positron emission tomography in vascular dementia: significance of white matter changes. J Neurol Sci. 2001;193(1):1–6.PubMedCrossRefGoogle Scholar
- 27.Akopov SE, Simonian NA, Grigorian GS. Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infarction and their correlation with brain tissue damage. Stroke. 1996;27(10):1739–43.PubMedGoogle Scholar
- 28.Spinelli F, Sara R, Milella M, Ruffini L, Sterzi R, Causarano IR, et al. Technetium-99 m hexamethylpropylene amine oxime leucocyte scintigraphy in the differential diagnosis of cerebral abscesses. Eur J Nucl Med. 2000;27(1):46–9.PubMedCrossRefGoogle Scholar
- 29.Murphy JM, Balan KK, Toms A, Gomez-Anson B, Lockwood M. Radiolabeled leucocyte imaging in diffuse granulomatous involvement of the meninges in Wegener’s granulomatosis: scintigraphic findings and their role in monitoring treatment response to specific immunotherapy (humanized monoclonal antilymphocyte antibodies). AJNR Am J Neuroradiol. 2000;21(8):1460–5.PubMedGoogle Scholar
- 30.Liberatore M, Drudi FM, Tarantino R, Prosperi D, Fiore V, Missori P, et al. Tc-99 m exametazime-labeled leukocyte scans in the study of infections in skull neurosurgery. Clin Nucl Med. 2003;28(12):971–4.PubMedCrossRefGoogle Scholar
- 31.Kermode AG, Tofts PS, Thompson AJ, MacManus DG, Rudge P, Kendall BE, et al. Heterogeneity of blood–brain barrier changes in multiple sclerosis: an MRI study with gadolinium-DTPA enhancement. Neurology. 1990;40(2):229–35.PubMedGoogle Scholar
- 32.Jander S, Schroeter M, Saleh A. Imaging inflammation in acute brain ischemia. Stroke. 2007;38(2 Suppl):642–5.PubMedCrossRefGoogle Scholar
- 33.Nighoghossian N, Wiart M, Cakmak S, Berthezene Y, Derex L, Cho TH, et al. Inflammatory response after ischemic stroke: a USPIO-enhanced MRI study in patients. Stroke. 2007;38(2):303–7.PubMedCrossRefGoogle Scholar
- 34.Nahrendorf M, Jaffer FA, Kelly KA, Sosnovik DE, Aikawa E, Libby P, et al. Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation. 2006;114(14):1504–11.PubMedCrossRefGoogle Scholar
- 35.Sibson NR, Blamire AM, Bernades-Silva M, Laurent S, Boutry S, Muller RN, et al. MRI detection of early endothelial activation in brain inflammation. Magn Reson Med. 2004;51(2):248–52.PubMedCrossRefGoogle Scholar
- 36.Shah F, Hume SP, Pike VW, Ashworth S, McDermott J. Synthesis of the enantiomers of [N-methyl-11C]PK11195 and comparison of their behaviours as radioligands for PK binding sites in rats. Nucl Med Biol. 1994;21(4):573–81.PubMedCrossRefGoogle Scholar
- 37.Petit-Taboue MC, Baron JC, Barre L, Travere JM, Speckel D, Camsonne R, et al. Brain kinetics and specific binding of [11C]PK11195 to omega 3 sites in baboons: positron emission tomography study. Eur J Pharmacol. 1991;200(2–3):347–51.PubMedCrossRefGoogle Scholar
- 38.Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BN, Luurtsema G, Windhorst AD, et al. Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies. J Cereb Blood Flow Metab. 2005;25(7):842–51.PubMedCrossRefGoogle Scholar
- 39.Kropholler MA, Boellaard R, Schuitemaker A, Folkersma H, van Berckel BN, Lammertsma AA. Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies. J Cereb Blood Flow Metab. 2006;26(11):1431–41.PubMedCrossRefGoogle Scholar
- 40.Kropholler MA, Boellaard R, van Berckel BN, Schuitemaker A, Kloet RW, Lubberink MJ, et al. Evaluation of reference regions for (R)-[11C]PK11195 studies in Alzheimer’s disease and mild cognitive impairment. J Cereb Blood Flow Metab. 2007;27(12):1965–74.PubMedCrossRefGoogle Scholar
- 41.Schuitemaker A, van Berckel BN, Kropholler MA, Veltman DJ, Scheltens P, Jonker C, et al. SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods. Neuroimage. 2007;35(4):1473–9.PubMedCrossRefGoogle Scholar
- 42.Schuitemaker A, van Berckel BN, Kropholler MA, Kloet RW, Jonker C, Scheltens P, et al. Evaluation of methods for generating parametric (R)-[11C]PK11195 binding images. J Cereb Blood Flow Metab. 2007;27(9):1603–15.PubMedCrossRefGoogle Scholar
- 43.Anderson AN, Pavese N, Edison P, Tai YF, Hammers A, Gerhard A, et al. A systematic comparison of kinetic modelling methods generating parametric maps for [(11)C]-(R)-PK11195. Neuroimage. 2007;36(1):28–37.PubMedCrossRefGoogle Scholar
- 44.Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, et al. Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med. 2007;48(1):158–67.PubMedGoogle Scholar
- 45.Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358(9280):461–7.PubMedCrossRefGoogle Scholar
- 46.Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 2006;21(2):404–12.PubMedCrossRefGoogle Scholar
- 47.Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, et al. Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology. 2006;66(11):1638–43.PubMedCrossRefGoogle Scholar
- 48.Price CJ, Wang D, Menon DK, Guadagno JV, Cleij M, Fryer T, et al. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke. 2006;37(7):1749–53.PubMedCrossRefGoogle Scholar
- 49.Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, 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):601–9.PubMedCrossRefGoogle Scholar
- 50.Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, 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;123:2321–37.PubMedCrossRefGoogle Scholar
- 51.Venneti S, Lopresti BJ, Wiley CA. The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol. 2006;80(6):308–22.PubMedCrossRefGoogle Scholar
- 52.Cagnin A, Gerhard A, Banati RB. In vivo imaging of neuroinflammation. Eur Neuropsychopharmacol. 2002;12(6):581–6.PubMedCrossRefGoogle Scholar
- 53.James ML, Selleri S, Kassiou M. Development of ligands for the peripheral benzodiazepine receptor. Curr Med Chem. 2006;13(17):1991–2001.PubMedCrossRefGoogle Scholar
- 54.Bergstrom M, Mosskin M, Ericson K, Ehrin E, Thorell JO, von Holst H, et al. Peripheral benzodiazepine binding sites in human gliomas evaluated with positron emission tomography. Acta Radiol Suppl. 1986;369:409–11.PubMedGoogle Scholar
- 55.Junck L, Olson JM, Ciliax BJ, Koeppe RA, Watkins GL, Jewett DM, et al. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol. 1989;26(6):752–8.PubMedCrossRefGoogle Scholar
- 56.Farges R, Joseph-Liauzun E, Shire D, Caput D, Le Fur G, Ferrara P. Site-directed mutagenesis of the peripheral benzodiazepine receptor: identification of amino acids implicated in the binding site of Ro5–4864. Mol Pharmacol. 1994;46(6):1160–7.PubMedGoogle Scholar
- 57.Van Dort ME, Ciliax BJ, Gildersleeve DL, Sherman PS, Rosenspire KC, Young AB, et al. Radioiodinated benzodiazepines: agents for mapping glial tumors. J Med Chem. 1988;31(11):2081–6.PubMedCrossRefGoogle Scholar
- 58.Shah F, Pike V, Turton DR. Syntheses of homochiral 11C-labelled radioligands for peripheral benzodiazepine binding sites. J Label Comp Radiopharm. 1993;32:166–8.Google Scholar
- 59.Pascali C, Luthra SK, Pike VW, Price GW, Ahier RG, Hume SP, et al. The radiosynthesis of [18F]PK14105 as an alternative radioligand for peripheral type benzodiazepine binding sites. Int J Rad Appl Instrum [A]. 1990;41(5):477–82.CrossRefGoogle Scholar
- 60.Price GW, Ahier RG, Hume SP, Myers R, Manjil L, Cremer JE, et al. In vivo binding to peripheral benzodiazepine binding sites in lesioned rat brain: comparison between [3H]PK11195 and [18F]PK14105 as markers for neuronal damage. J Neurochem. 1990;55(1):175–85.PubMedCrossRefGoogle Scholar
- 61.Yu W, Wang E, Voll RJ, Miller AH, Goodman MM. 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;16(11):6145–55.PubMedCrossRefGoogle Scholar
- 62.Gildersleeve DL, Van Dort ME, Johnson JW, Sherman PS, Wieland DM. Synthesis and evaluation of [123I]-iodo-PK11195 for mapping peripheral-type benzodiazepine receptors (omega 3) in heart. Nucl Med Biol. 1996;23(1):23–8.PubMedCrossRefGoogle Scholar
- 63.Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, et al. Assessment of neuroinflammation and microglial activation in Alzheimer’s disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur Neurol 2003;50(1):39–47.Google Scholar
- 64.Matarrese M, Moresco RM, Cappelli A, Anzini M, Vomero S, Simonelli P, 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;44(4):579–85.PubMedCrossRefGoogle Scholar
- 65.Belloli S, Moresco RM, Matarrese M, Biella G, Sanvito F, Simonelli P, et al. Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration. Neurochem Int. 2004;44(6):433–40.PubMedCrossRefGoogle Scholar
- 66.Cappelli A, Matarrese M, Moresco RM, Valenti S, Anzini M, Vomero S, 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;14(12):4055–66.PubMedCrossRefGoogle Scholar
- 67.Primofiore G, Da Settimo F, Taliani S, Simorini F, Patrizi MP, Novellino E, et al. N,N-dialkyl-2-phenylindol-3-ylglyoxylamides. A new class of potent and selective ligands at the peripheral benzodiazepine receptor. J Med Chem. 2004;47(7):1852–5.PubMedCrossRefGoogle Scholar
- 68.Bennacef I, Haile CN, Schmidt A, Koren AO, Seibyl JP, Staley JK, et al. Synthesis and receptor binding studies of halogenated N,N-dialkylel-(2-phenyl-1H-indol-3-yl)glyoxylamides to visualize peripheral benzodiazepine receptors with SPECT or PET. Bioorg Med Chem. 2006;14(22):7582–91.PubMedCrossRefGoogle Scholar
- 69.Romeo E, Auta J, Kozikowski AP, Ma D, Papadopoulos V, Puia G, 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;262(3):971–8.PubMedGoogle Scholar
- 70.Ferzaz B, Brault E, Bourliaud G, Robert JP, Poughon G, Claustre Y, 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;301(3):1067–78.PubMedCrossRefGoogle Scholar
- 71.Homes TP, Mattner F, Keller PA, Katsifis A. Synthesis and in vitro binding of N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides for the peripheral benzodiazepine binding sites. Bioorg Med Chem. 2006;14(11):3938–46.PubMedCrossRefGoogle Scholar
- 72.Homes TP, Mattner F, Keller PA, Katsifis A. Synthesis and in vivo evaluation of a novel [123I]indolglyoxylamide for the peripheral benzodiazepine binding sites. J Label Comp Radiopharm. 2007;50:S307.Google Scholar
- 73.Gulyas B, Halldin C, Karlsson P, Chou YH, Swahn CG, Bonock P, et al. Brain uptake and plasma metabolism of [11C]vinpocetine: a preliminary PET study in a cynomolgus monkey. J Neuroimaging. 1999;9(4):217–22.PubMedGoogle Scholar
- 74.Gulyas B, Halldin C, Sandell J, Karlsson P, Sovago J, Karpati E, et al. PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects. Acta Neurol Scand. 2002;106(6):325–32.PubMedCrossRefGoogle Scholar
- 75.Gulyas B, Halldin C, Vas A, Banati RB, Shchukin E, Finnema S, et al. [11C]vinpocetine: a prospective peripheral benzodiazepine receptor ligand for primate PET studies. J Neurol Sci. 2005;229-230:219–23.PubMedCrossRefGoogle Scholar
- 76.Gulyas B, Vas A, Halldin C, Sovago J, Sandell J, Olsson H, et al. Cerebral uptake of [ethyl-11C]vinpocetine and 1-[11C]ethanol in cynomolgous monkeys: a comparative preclinical PET study. Nucl Med Biol. 2002;29(7):753–9.PubMedCrossRefGoogle Scholar
- 77.Gulyas B, Halldin C, Sovago J, Sandell J, Cselenyi Z, Vas A, et al. Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine. Eur J Nucl Med Mol Imaging. 2002;29(8):1031–8.PubMedCrossRefGoogle Scholar
- 78.Vas A, Shchukin Y, Karrenbauer VD, Cselenyi Z, Kostulas K, Hillert J, 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.PubMedCrossRefGoogle Scholar
- 79.Kita A, Kohayakawa H, Kinoshita T, Ochi Y, Nakamichi K, Kurumiya S, et al. Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand. Br J Pharmacol. 2004;142(7):1059–72.PubMedCrossRefGoogle Scholar
- 80.Amitani M, Zhang MR, Noguchi J, Kumata K, Ito T, Takai N, et al. Blood flow dependence of the intratumoral distribution of peripheral benzodiazepine receptor binding in intact mouse fibrosarcoma. Nucl Med Biol. 2006;33(8):971–5.PubMedCrossRefGoogle Scholar
- 81.Zhang MR, Kumata K, Maeda J, Yanamoto K, Hatori A, Okada M, et al. 11C-AC-5216: a novel PET ligand for peripheral benzodiazepine receptors in the primate brain. J Nucl Med. 2007;48(11):1853–61.PubMedCrossRefGoogle Scholar
- 82.Yanamoto K, Zhang MR, Kumata K, Hatori A, Okada M, Suzuki K. In vitro and ex vivo autoradiography studies on peripheral-type benzodiazepine receptor binding using [11C]AC-5216 in normal and kainic acid-lesioned rats. Neurosci Lett. 2007;428(2–3):59–63.PubMedCrossRefGoogle Scholar
- 83.Zhang MR, Kida T, Noguchi J, Furutsuka K, Maeda J, Suhara T, et al. [11C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. Nucl Med Biol. 2003;30(5):513–9.PubMedCrossRefGoogle Scholar
- 84.Maeda J, Suhara T, Zhang MR, Okauchi T, Yasuno F, Ikoma Y, et al. Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain. Synapse. 2004;52(4):283–91.PubMedCrossRefGoogle Scholar
- 85.Probst KC, Izquierdo D, Bird JL, Brichard L, Franck D, Davies JR, et al. Strategy for improved [11C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [11C]DAA1106. Nucl Med Biol. 2007;34(4):439–46.PubMedCrossRefGoogle Scholar
- 86.Venneti S, Wagner AK, Wang G, Slagel SL, Chen X, Lopresti BJ, 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):118–27.PubMedCrossRefGoogle Scholar
- 87.Venneti S, Lopresti BJ, Wang G, Slagel SL, Mason NS, Mathis CA, et al. A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation. J Neurochem. 2007;102(6):2118–31.PubMedCrossRefGoogle Scholar
- 88.Zhang MR, Ogawa M, Maeda J, Ito T, Noguchi J, Kumata K, et al. [2-11C]isopropyl-, [1–11C]ethyl-, and [11C]methyl-labeled phenoxyphenyl acetamide derivatives as positron emission tomography ligands for the peripheral benzodiazepine receptor: radiosynthesis, uptake, and in vivo binding in brain. J Med Chem. 2006;49(9):2735–42.PubMedCrossRefGoogle Scholar
- 89.Briard E, Hong J, Musachio JL, Zoghbi SS, Fujita M, Imaizumi M, et al. Synthesis and evaluation of two candidate 11C-labeled radioligands for brain peripheral benzodiazepine receptors. J Label Comp Radiopharm. 2005;48:S71.Google Scholar
- 90.Imaizumi M, Briard E, Zoghbi SS, Gourley JP, Hong J, Musachio JL, et al. Kinetic evaluation in nonhuman primates of two new PET ligands for peripheral benzodiazepine receptors in brain. Synapse. 2007;61(8):595–605.PubMedCrossRefGoogle Scholar
- 91.Briard E, Zoghbi SS, Imaizumi M, Gourley JP, Shetty HU, Hong J, et al. Synthesis and evaluation in monkey of two sensitive (11)C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo. J Med Chem. 2008;51(1):17–30.PubMedCrossRefGoogle Scholar
- 92.Imaizumi M, Briard E, Zoghbi SS, Gourley JP, Hong J, Fujimura Y, et al. Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors. Neuroimage. 2008;39(3):1289–98.PubMedCrossRefGoogle Scholar
- 93.Imaizumi M, Kim HJ, Zoghbi SS, Briard E, Hong J, Musachio JL, et al. PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci Lett. 2007;411(3):200–5.PubMedCrossRefGoogle Scholar
- 94.Wilson AA, Garcia A, Parkes J, McCormick P, Stephenson KA, Houle S, et al. Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors. Nucl Med Biol. 2008;35(3):305–14.PubMedCrossRefGoogle Scholar
- 95.Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, et al. Imaging brain inflammation with [11C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab. 2007;27(12):1975–86.PubMedCrossRefGoogle Scholar
- 96.Zhang MR, Kumata K, Maeda J, Haradahira T, Noguchi J, Suhara T, et al. N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[131I]iodo-5-methoxybenzyl)acetamide: a potent iodinated radioligand for the peripheral-type benzodiazepine receptor in brain. J Med Chem. 2007;50(4):848–55.PubMedCrossRefGoogle Scholar
- 97.Zhang M-R, Kumata K, Suzuki K. Practical synthesis of [18F]fluorobenzene starting from phenyltributylstanne. J Label Comp Radiopharm. 2007;50:S152.CrossRefGoogle Scholar
- 98.Zhang MR, Maeda J, Furutsuka K, Yoshida Y, Ogawa M, Suhara T, et al. [18F]FMDAA1106 and [18F]FEDAA1106: two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR). Bioorg Med Chem Lett. 2003;13(2):201–4.PubMedCrossRefGoogle Scholar
- 99.Zhang MR, Maeda J, Ogawa M, Noguchi J, Ito T, Yoshida Y, et al. Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. J Med Chem. 2004;47(9):2228–35.PubMedCrossRefGoogle Scholar
- 100.Zhang MR, Maeda J, Ito T, Okauchi T, Ogawa M, Noguchi J, et al. Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor. Bioorg Med Chem. 2005;13(5):1811–8.PubMedCrossRefGoogle Scholar
- 101.Maeda J, Higuchi M, Inaji M, Ji B, Haneda E, Okauchi T, et al. Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res. 2007;1157:100–11.PubMedCrossRefGoogle Scholar
- 102.Maeda J, Ji B, Irie T, Tomiyama T, Maruyama M, Okauchi T, et al. Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer’s disease enabled by positron emission tomography. J Neurosci. 2007;27(41):10957–68.PubMedCrossRefGoogle Scholar
- 103.Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M, Toyama H, et al. Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [11C]DAA1106. J Cereb Blood Flow Metab. 2007;27(1):173–84.PubMedCrossRefGoogle Scholar
- 104.Fujimura Y, Ikoma Y, Yasuno F, Suhara T, Ota M, Matsumoto R, et al. Quantitative analyses of 18F-FEDAA1106 binding to peripheral benzodiazepine receptors in living human brain. J Nucl Med. 2006;47(1):43–50.PubMedGoogle Scholar
- 105.Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage. 2008;40(1):43–52.PubMedCrossRefGoogle Scholar
- 106.Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK, et al. Increased Binding of Peripheral Benzodiazepine Receptor in Alzheimer’s Disease Measured by Positron Emission Tomography with [(11)C]DAA1106. Biological psychiatry. 2008; advance online publication 2008 May 29. doi: 10.1016/j.biopsych.2008.04.021.
- 107.Mattner F, Mardon K, Loc’h C, Katsifis A. Pharmacological evaluation of an [123I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors. Life Sci. 2006;79(3):287–94.PubMedCrossRefGoogle Scholar
- 108.Katsifis A, Mattner F, Dikic B, Papazian V. Synthesis of substituted [123I]imidazo[1,2-a]pyridines as potential probes for the study of the peripheral benzodiazepine receptors using SPECT. Radiochim Acta. 2000;88(3–4):229–32.CrossRefGoogle Scholar
- 109.Mattner F, Katsifis A, Staykova M, Ballantyne P, Willenborg DO. Evaluation of a radiolabelled peripheral benzodiazepine receptor ligand in the central nervous system inflammation of experimental autoimmune encephalomyelitis: a possible probe for imaging multiple sclerosis. Eur J Nucl Med Mol Imaging. 2005;32(5):557–63.PubMedCrossRefGoogle Scholar
- 110.Katsifis A, Mattner F, Chapman J, Izard B, Papazian V, Dikic B, et al. Synthesis and evaluation of [123I]-labelled peripheral benzodiazepine receptor ligands in tumour bearing rodents. Eur J Nucl Med Mol Imaging. 2002;29:S163.CrossRefGoogle Scholar
- 111.Katsifis A, Mattner F, Papazian V, Chapman J. Ex vivo pharmacological evaluation of the peripheral benzodiazepine receptor radioligand [123I]-CLINDE in animal tumour models. J Label Comp Radiopharm. 2003;46:S9.Google Scholar
- 112.Pham T, Mattner F, Fookes C, Greguric I, Berghofer P, Ballantyne CM, et al. Synthesis and evaluation of [18F] labelled imidazopyridines, for the study of peripheral benzodiazepine binding sites using PET. J Label Comp Radiopharm. 2007;50:S377.Google Scholar
- 113.Thominiaux C, Mattner F, Greguric I, Boutin H, Chauveau F, Kuhnast B, et al. Radiosynthesis of 2-[6-chloro-2-(4-iodophenyl)imidazo[1,2-a]pyridin-3-yl]-N-ethyl-N-[11C]methyl-acetamide, [11C]CLINME, a novel radioligand for imaging the peripheral benzodiazepine receptors with PET. J Label Comp Radiopharm. 2007;50(4):229–36.CrossRefGoogle Scholar
- 114.Boutin H, Chauveau F, Thominiaux C, Kuhnast B, Gregoire MC, Jan S, et al. In vivo imaging of brain lesions with [11C]CLINME, a new PET radioligand of peripheral benzodiazepine receptors. Glia. 2007;55(14):1459–68.PubMedCrossRefGoogle Scholar
- 115.Mattner F, Pham T, Greguric I, Berghofer P, Ballantyne CM, Liu X, et al. Labelling and in vivo evaluation of the [123I] labelled imidazopyridine-3-acetamide, CLINME, for the study of peripheral benzodiazepine binding sites. J Label Comp Radiopharm. 2007;50:S31.Google Scholar
- 116.Serra M, Madau P, Chessa MF, Caddeo M, Sanna E, Trapani G, et al. 2-Phenyl-imidazo[1,2-a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats. Br J Pharmacol. 1999;127(1):177–87.PubMedCrossRefGoogle Scholar
- 117.Sekimata K, Hatano K, Ogawa M, Abe J, Magata Y, Biggio G, et al. Radiosynthesis and in vivo evaluation of N-[11C]methylated imidazopyridineacetamides as PET tracers for peripheral benzodiazepine receptors. Nucl Med Biol. 2008;35(3):327–34.PubMedCrossRefGoogle Scholar
- 118.Katsifis A, Barlin G, Mattner F, Dikic B. Synthesis of [123I]iodine labelled imidazo[1,2-b] pyridazines as potential probes for the study of peripheral benzodiazepine receptors using SPECT. Radiochim Acta. 2004:305–309.Google Scholar
- 119.Pham T, Fookes C, Liu X, Greguric I, Bourdier T, Katsifis A. Synthesis of [18F]fluorine labelled imidazo[1,2b]pyridazine as potential probes the study of peripheral benzodiazepine binding sites using PET. J Label Comp Radiopharm. 2007;50:S204.Google Scholar
- 120.Mattner F, Pham T, Fookes C, Greguric I, Berghofer P, Ballantyne CM, et al. In vivo evaluation of a 18F-labelled imidazopyridazine, for the study of peripheral benzodiazepine binding sites using PET. J Label Comp Radiopharm. 2007;50:S76.Google Scholar
- 121.James ML, Fulton RR, Henderson DJ, Eberl S, Meikle SR, Thomson S, et al. Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand. Bioorg Med Chem. 2005;13(22):6188–94.PubMedCrossRefGoogle Scholar
- 122.Thominiaux C, Dolle F, James ML, Bramoulle Y, Boutin H, Besret L, et al. Improved synthesis of the peripheral benzodiazepine receptor ligand [11C]DPA-713 using [11C]methyl triflate. Appl Radiat Isot. 2006;64(5):570–3.PubMedCrossRefGoogle Scholar
- 123.Bennacef I, Salinas CA, Jensen SB, Cunningham VJ, Bonasera TA, Gee AD. [11C]DPA713: radiosynthesis and evaluation for cerebral peripheral benzodiazepine receptor imaging. J Label Comp Radiopharm. 2007;50:S341.Google Scholar
- 124.Creelman A, Thominiaux C, Chauveau F, Fulton R, Kuhnast B, Henderson D, et al. Synthesis and evaluation of the translocator protein (18 kDa) (TSPO) ligand [11C]DPA715 in rat and non-human primate. J Label Comp Radiopharm. 2007;50:S354.CrossRefGoogle Scholar
- 125.James ML, Fulton RR, Vercoullie J, Henderson DJ, Garreau L, Chalon S, et al. DPA-714, a New translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic Characterization. J Nucl Med. 2008;49(5):814–22.PubMedCrossRefGoogle Scholar
- 126.Boutin H, Chauveau F, Thominiaux C, Gregoire MC, James ML, Trebossen R, et al. 11C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J Nucl Med. 2007;48(4):573–81.PubMedCrossRefGoogle Scholar
- 127.Doorduin J, Vellinga NAR, Klein HC, Kassiou M, James M, Dierckx RA, et al. PET imaging of neuroinflammation in a rat model of herpes encephalitis: a comparison of [11C]-(R)-PK11195 and [11C]-DPA-713. Eur J Nucl Med Mol Imaging. 2006;33:S192.Google Scholar
- 128.Doorduin J, Klein HC, James M, Kassiou M, Dierckx R, de Vries EF. [18F]DPA-714 as a novel PET tracer for PBR: a comparison with [11C]PK11195 in a rat model of HSV encephalitis. J Label Comp Radiopharm. 2007;50:S333.CrossRefGoogle Scholar
- 129.Rao VL, Butterworth RF. Characterization of binding sites for the omega3 receptor ligands [3H]PK11195 and [3H]RO5–4864 in human brain. Eur J Pharmacol. 1997;340(1):89–99.PubMedCrossRefGoogle Scholar
- 130.Protocol number 07-M-0129 http://clinicalstudies.info.nih.gov/cgi/wais/bold032001.pl?B_07-M-0129.html@PBR28, accessed September 18, 2008.
- 131.Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC, et al. Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J Neurovirol. 2005;11(4):346–55.PubMedCrossRefGoogle Scholar
- 132.Wiley CA, Lopresti BJ, Becker JT, Boada F, Lopez OL, Mellors J, et al. Positron emission tomography imaging of peripheral benzodiazepine receptor binding in human immunodeficiency virus-infected subjects with and without cognitive impairment. J Neurovirol. 2006;12(4):262–71.PubMedCrossRefGoogle Scholar
- 133.Benavides J, Quarteronet D, Imbault F, Malgouris C, Uzan A, Renault C, et al. Labelling of “peripheral–type” benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization. J Neurochem. 1983;41(6):1744–50.PubMedCrossRefGoogle Scholar
- 134.Beal MF, Ferrante RJ, Swartz KJ, Kowall NW. Chronic quinolinic acid lesions in rats closely resemble Huntington’s disease. J Neurosci. 1991;11(6):1649–59.PubMedGoogle Scholar
- 135.Bolton SJ, Perry VH. Differential blood–brain barrier breakdown and leucocyte recruitment following excitotoxic lesions in juvenile and adult rats. Exp Neurol. 1998;154(1):231–40.PubMedCrossRefGoogle Scholar
- 136.Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain. 2006;129(Pt 8):1972–83.PubMedCrossRefGoogle Scholar
- 137.von Horsten S, Schmitt I, Nguyen HP, Holzmann C, Schmidt T, Walther T, et al. Transgenic rat model of Huntington’s disease. Hum Mol Genet. 2003;12(6):617–24.CrossRefGoogle Scholar
- 138.Regulier E, Trottier Y, Perrin V, Aebischer P, Deglon N. Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant in rat striatum. Hum Mol Genet. 2003;12(21):2827–36.PubMedCrossRefGoogle Scholar
- 139.Chen MK, Guilarte TR. Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Ther. 2008;118(1):1–17.PubMedCrossRefGoogle Scholar
- 140.Saavedra JM, Pavel J. The discovery of a novel macrophage binding site. Cell Mol Neurobiol. 2006;26(4–6):507–24.CrossRefGoogle Scholar
- 141.Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y. Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke. 2001;32(5):1208–15.PubMedGoogle Scholar
- 142.Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290(5497):1768–71.PubMedCrossRefGoogle Scholar
- 143.Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Takahashi H, Imai Y, et al. Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion. Neurosci Lett. 2007;418(1):44–8.PubMedCrossRefGoogle Scholar
- 144.Babcock AA, Wirenfeldt M, Holm T, Nielsen HH, Dissing-Olesen L, Toft-Hansen H, et al. Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation. J Neurosci. 2006;26(49):12826–37.PubMedCrossRefGoogle Scholar
- 145.Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002;39(3):279–91.PubMedCrossRefGoogle Scholar
- 146.Rosi S, Pert CB, Ruff MR, McGann-Gramling K, Wenk GL. Chemokine receptor 5 antagonist D-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer’s disease. Neuroscience. 2005;134(2):671–6.PubMedCrossRefGoogle Scholar
- 147.Barber PA, Foniok T, Kirk D, Buchan AM, Laurent S, Boutry S, et al. MR molecular imaging of early endothelial activation in focal ischemia. Ann Neurol. 2004;56(1):116–20.PubMedCrossRefGoogle Scholar
- 148.Peterson JW, Bo L, Mork S, Chang A, Ransohoff RM, Trapp BD. VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions. J Neuropathol Exp Neurol. 2002;61(6):539–46.PubMedGoogle Scholar
- 149.Justicia C, Martin A, Rojas S, Gironella M, Cervera A, Panes J, et al. Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. J Cereb Blood Flow Metab. 2006;26(3):421–32.PubMedCrossRefGoogle Scholar
- 150.Reinhardt M, Hauff P, Linker RA, Briel A, Gold R, Rieckmann P, et al. Ultrasound derived imaging and quantification of cell adhesion molecules in experimental autoimmune encephalomyelitis (EAE) by Sensitive Particle Acoustic Quantification (SPAQ). Neuroimage. 2005;27(2):267–78.PubMedCrossRefGoogle Scholar
- 151.Kielian T, Esen N. Effects of neuroinflammation on glia-glia gap junctional intercellular communication: a perspective. Neurochem Int. 2004;45(2–3):429–36.PubMedCrossRefGoogle Scholar
- 152.Brand-Schieber E, Werner P, Iacobas DA, Iacobas S, Beelitz M, Lowery SL, et al. Connexin43, the major gap junction protein of astrocytes, is down-regulated in inflamed white matter in an animal model of multiple sclerosis. J Neurosci Res. 2005;80(6):798–808.PubMedCrossRefGoogle Scholar
- 153.Margaill I, Royer J, Lerouet D, Ramauge M, Le Goascogne C, Li WW, et al. Induction of type 2 iodothyronine deiodinase in astrocytes after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 2005;25(4):468–76.PubMedCrossRefGoogle Scholar
- 154.Uppoor RS, Mummaneni P, Cooper E, Pien HH, Sorensen AG, Collins J, et al. The Use of Imaging in the Early Development of Neuropharmacological Drugs: A Survey of Approved NDAs. Clin Pharmacol Ther. 2007;84:69–74.Google Scholar