{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:14:51Z","timestamp":1790788491302,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T00:00:00Z","timestamp":1686009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Targeting neuroinflammation, and in particular, microglial activation and astrocytosis, is a current area of the focus of new treatment interventions for a number of neurodegenerative disorders. Probing the roles of microglia and astrocytes in human disease requires the development of useful tools, such as PET imaging tools that are specific for the cell type(s) of interest. This review concentrates on the recent advances in the development of Imidazoline2 binding site (I2BS) PET tracers, which are purported to target astrocytes, and hence could represent key clinical imaging tools for targeting astrocytes in neurodegenerative disease. Five PET tracers for the I2BS are described in this review, with only one (11C-BU99008) being currently validated to GMP for clinical use, and data reported from healthy volunteers, Alzheimer\u2019s disease patients, and Parkinson\u2019s disease patients. The clinical data utilising 11C-BU99008 have revealed the potential early involvement of astrogliosis in neurodegeneration that might precede the activation of microglia, which, if confirmed, could provide a vital new means for potentially targeting neurodegeneration earlier in the disease course.<\/jats:p>","DOI":"10.3390\/ijms24129787","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T02:57:30Z","timestamp":1686020250000},"page":"9787","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Imidazoline-I2 PET Tracers in Neuroimaging"],"prefix":"10.3390","volume":"24","author":[{"given":"Christine A.","family":"Parker","sequence":"first","affiliation":[{"name":"Neuropsychopharmacology Unit, Division of Psychiatry, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK"},{"name":"GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1286-1401","authenticated-orcid":false,"given":"David J.","family":"Nutt","sequence":"additional","affiliation":[{"name":"Neuropsychopharmacology Unit, Division of Psychiatry, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin J.","family":"Tyacke","sequence":"additional","affiliation":[{"name":"Neuropsychopharmacology Unit, Division of Psychiatry, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1124\/pr.118.016311","article-title":"Imidazoline Receptor System: The Past, the Present, and the Future","volume":"72","author":"Bousquet","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.nucmedbio.2011.07.008","article-title":"PET study using [11C]FTIMD with ultra-high specific activity to evaluate I2-imidazoline receptors binding in rat brains","volume":"39","author":"Kawamura","year":"2012","journal-title":"Nucl. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.nucmedbio.2010.02.013","article-title":"Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD)","volume":"37","author":"Kawamura","year":"2010","journal-title":"Nucl. Med. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.nucmedbio.2014.12.014","article-title":"In vivo evaluation of a new (1)(8)F-labeled PET ligand, [(1)(8)F]FEBU, for the imaging of I(2)-imidazoline receptors","volume":"42","author":"Kawamura","year":"2015","journal-title":"Nucl. Med. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2967\/jnumed.112.108258","article-title":"Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008","volume":"54","author":"Kealey","year":"2013","journal-title":"J. Nucl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/syn.20897","article-title":"In vivo and in vitro imaging of I(2) imidazoline receptors in the monkey brain","volume":"65","author":"Kawamura","year":"2011","journal-title":"Synapse"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nucmedbio.2016.10.005","article-title":"A useful PET probe [(11)C]BU99008 with ultra-high specific radioactivity for small animal PET imaging of I2-imidazoline receptors in the hypothalamus","volume":"45","author":"Kawamura","year":"2017","journal-title":"Nucl. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"838","DOI":"10.2967\/jnumed.113.131854","article-title":"Evaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brain","volume":"55","author":"Parker","year":"2014","journal-title":"J. Nucl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.2967\/jnumed.118.208009","article-title":"Evaluation of (11)C-BU99008, a PET Ligand for the Imidazoline2 Binding Site in Human Brain","volume":"59","author":"Tyacke","year":"2018","journal-title":"J. Nucl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13550-018-0429-x","article-title":"First evaluation of PET-based human biodistribution and radiation dosimetry of (11)C-BU99008, a tracer for imaging the imidazoline2 binding site","volume":"8","author":"Venkataraman","year":"2018","journal-title":"EJNMMI Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5848","DOI":"10.1038\/s41380-021-01193-z","article-title":"Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using (11)C-BU99008 PET and its relationship with amyloid load","volume":"26","author":"Calsolaro","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1038\/s41380-021-01429-y","article-title":"Relationship between astrocyte reactivity, using novel (11)C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals","volume":"27","author":"Livingston","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"fcac199","DOI":"10.1093\/braincomms\/fcac199","article-title":"Astrogliosis in aging and Parkinson\u2019s disease dementia: A new clinical study with (11)C-BU99008 PET","volume":"4","author":"Mohamed","year":"2022","journal-title":"Brain Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1093\/brain\/awz260","article-title":"Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson\u2019s disease: An in vivo11C-BU99008 PET study","volume":"142","author":"Wilson","year":"2019","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1002\/syn.21541","article-title":"Evaluation and initial in vitro and ex vivo characterization of the potential positron emission tomography ligand, BU99008 (2-(4,5-dihydro-1H-imidazol-2-yl)-1-methyl-1H-indole), for the imidazoline(2) binding site","volume":"66","author":"Tyacke","year":"2012","journal-title":"Synapse"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/S0968-0896(00)00280-7","article-title":"Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands","volume":"9","author":"Anastassiadou","year":"2001","journal-title":"Bioorg. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1016\/S0968-0896(98)80005-9","article-title":"Ligand binding to I2 imidazoline receptor: The role of lipophilicity in quantitative structure-activity relationship models","volume":"6","author":"Pigini","year":"1998","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5130","DOI":"10.1021\/jm800400k","article-title":"Novel ligands rationally designed for characterizing I2-imidazoline binding sites nature and functions","volume":"51","author":"Gentili","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S127","DOI":"10.1016\/j.neuroimage.2010.04.104","article-title":"Synthesis and in vivo evaluation of [11C]BU99008 as a ligand for the imidazoline I2 binding site","volume":"52","author":"Kealey","year":"2010","journal-title":"NeuroImage"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1749-6632.1995.tb32397.x","article-title":"Functional studies of specific imidazoline-2 receptor ligands","volume":"763","author":"Nutt","year":"1995","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s11307-018-1206-y","article-title":"Change in the Binding of [(11)C]BU99008 to Imidazoline I2 Receptor Using Brain PET in Zucker Rats","volume":"21","author":"Kawamura","year":"2019","journal-title":"Mol. Imaging Biol. MIB Off. Publ. Acad. Mol. Imaging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1196\/annals.1304.039","article-title":"Novel ligands for the investigation of imidazoline receptors and their binding proteins","volume":"1009","author":"Hudson","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.nucmedbio.2011.06.001","article-title":"Synthesis and evaluation of PET probes for the imaging of I2 imidazoline receptors in peripheral tissues","volume":"39","author":"Kawamura","year":"2012","journal-title":"Nucl. Med. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/j.1476-5381.1994.tb14842.x","article-title":"The effects of chronic imidazoline drug treatment on glial fibrillary acidic protein concentrations in rat brain","volume":"111","author":"Olmos","year":"1994","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1111\/j.1471-4159.1993.tb03599.x","article-title":"Opposite age-dependent changes of alpha 2A-adrenoceptors and nonadrenoceptor [3H]idazoxan binding sites (I2-imidazoline sites) in the human brain: Strong correlation of I2 with monoamine oxidase-B sites","volume":"61","author":"Sastre","year":"1993","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5833","DOI":"10.1038\/s41380-021-01101-5","article-title":"Astroglial tracer BU99008 detects multiple binding sites in Alzheimer\u2019s disease brain","volume":"26","author":"Kumar","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"37","DOI":"10.2967\/jnumed.110.087031","article-title":"Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: A multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG","volume":"53","author":"Carter","year":"2012","journal-title":"J. Nucl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/BF01255819","article-title":"Localization of monoamine oxidase B in human brain by autoradiographical use of 11C-labelled L-deprenyl","volume":"77","author":"Jossan","year":"1989","journal-title":"J. Neural Transm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/jnc.15565","article-title":"Reactive astrogliosis: A friend or foe in the pathogenesis of Alzheimer\u2019s disease","volume":"164","author":"Kumar","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Werry, E.L., Bright, F.M., Piguet, O., Ittner, L.M., Halliday, G.M., Hodges, J.R., Kiernan, M.C., Loy, C.T., Kril, J.J., and Kassiou, M. (2019). Recent Developments in TSPO PET Imaging as A Biomarker of Neuroinflammation in Neurodegenerative Disorders. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133161"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.bbi.2021.05.025","article-title":"Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation","volume":"96","author":"Singh","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"683","DOI":"10.2967\/jnumed.118.216747","article-title":"(18)F-JNJ-64413739, a Novel PET Ligand for the P2X7 Ion Channel: Radiation Dosimetry, Kinetic Modeling, Test-Retest Variability, and Occupancy of the P2X7 Antagonist JNJ-54175446","volume":"60","author":"Koole","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13550-022-00929-4","article-title":"First-in-human use of (11)C-CPPC with positron emission tomography for imaging the macrophage colony-stimulating factor 1 receptor","volume":"12","author":"Coughlin","year":"2022","journal-title":"EJNMMI Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9787\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:48:56Z","timestamp":1760125736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,6]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24129787"],"URL":"https:\/\/doi.org\/10.3390\/ijms24129787","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,6]]}}}