Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study.

Owen, David R, Guo, Qi, Kalk, Nicola J, Colasanti, Alessandro, Kalogiannopoulou, Dimitra, Dimmer, Rahul, Lewis, Yvonne L, Libri, Vincenzo, Barletta, Julien, Ramada-Magalhaes, Joaquim, Kamalakaran, Aruloly, Nutt, David J, Passchier, Jan, Matthews, Paul M, Gunn, Roger N and Rabiner, Eugenii A (2014) Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study. Journal of Cerebral Blood Flow and Metabolism, 34 (6). pp. 989-994. ISSN 0271-678X

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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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry
R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0438 Psychiatry
Depositing User: Christina Lee
Date Deposited: 31 May 2019 11:22
Last Modified: 01 Jul 2019 13:46
URI: http://sro.sussex.ac.uk/id/eprint/84032

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