Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

• Published in: Journal of cerebral blood flow and metabolism Vol. 34; no. 6; pp. 989 - 994
• Main Authors: Owen, David R, Guo, Qi, Kalk, Nicola J, Colasanti, Alessandro, Kalogiannopoulou, Dimitra, Dimber, Rahul, Lewis, Yvonne L, Libri, Vincenzo, Barletta, Julien, Ramada-Magalhaes, Joaquim, Kamalakaran, Aruloly, Nutt, David J, Passchier, Jan, Matthews, Paul M, Gunn, Roger N, Rabiner, Eugenii A
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.06.2014; Sage Publications Ltd; Nature Publishing Group
• Subjects: Acetamides - administration & dosage; Adult; Brain - diagnostic imaging; Brain - metabolism; Carbon Isotopes - administration & dosage; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Humans; Male; Original; Positron-Emission Tomography; Purines - administration & dosage; Pyridines - administration & dosage; Radiography; Receptors, GABA - metabolism; [11C]PBR28; TSPO; specific binding; rs6971 polymorphism; emapunil; XBD173
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2014.46

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 [11C]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 [11C]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 [11C]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.