title: Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study.
abstract: Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BPND). Here, we used blockade of the TSPO radioligand [(11)C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (VND), and hence estimate the BPND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [(11)C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, VND was estimated via the occupancy plot. Values of BPND for all subjects were calculated using this VND estimate. Total volume of distribution (VT) of MABs (2.94±0.31) was lower than VT of HABs (4.33±0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50=0.34±0.13 mg/kg). The occupancy plot provided a VND estimate of 1.98 (1.69, 2.26). Based on these VND estimates, BPND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [(11)C]PBR28 VND and hence BPND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating VND for TSPO targeting radioligands.
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College, London, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Owen
authors.affiliation: 1] Division of Brain Sciences, Department of Medicine, Imperial College, London, UK [2] Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London, London, UK [3] Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: 1] Division of Brain Sciences, Department of Medicine, Imperial College, London, UK [2] Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Kalk
authors.affiliation: 1] Division of Brain Sciences, Department of Medicine, Imperial College, London, UK [2] Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colasanti
authors.affiliation: NIHR-Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, UK.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kalogiannopoulou
authors.affiliation: Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Dimber
authors.affiliation: Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Lewis
authors.affiliation: NIHR-Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Libri
authors.affiliation: Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Julien
authors.initials: J
authors.lastname: Barletta
authors.affiliation: Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ramada-Magalhaes
authors.affiliation: Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Aruloly
authors.initials: A
authors.lastname: Kamalakaran
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nutt
authors.affiliation: Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Passchier
authors.affiliation: 1] Division of Brain Sciences, Department of Medicine, Imperial College, London, UK [2] Neurosciences Therapeutic Area Unit, GlaxoSmithKline Research & Development, Brentford, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.affiliation: 1] Division of Brain Sciences, Department of Medicine, Imperial College, London, UK [2] Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: 1] Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London, London, UK [2] Imanova, Centre for Imaging Sciences, London, UK.
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
mesh_terms: D000081:Acetamides / Q000008:administration & dosage*; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002247:Carbon Isotopes / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D011687:Purines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D011859:Radiography; D018079:Receptors, GABA / Q000378:metabolism*
chemical_list: D000081:Acetamides; D002247:Carbon Isotopes; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011687:Purines; D011725:Pyridines; D018079:Receptors, GABA; C499229:TSPO protein, human