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

TY - JOUR

T1 - Determination of [(11)C]PBR28 binding potential in vivo

T2 - a first human TSPO blocking study

AU - Owen, David R.

AU - Guo, Qi

AU - Kalk, Nicola J.

AU - Colasanti, Alessandro

AU - Kalogiannopoulou, Dimitra

AU - Dimber, Rahul

AU - Lewis, Yvonne L.

AU - Libri, Vincenzo

AU - Barletta, Julien

AU - Ramada-Magalhaes, Joaquim

AU - Kamalakaran, Aruloly

AU - Nutt, David J.

AU - Passchier, Jan

AU - Matthews, Paul M.

AU - Gunn, Roger N.

AU - Rabiner, Eugenii A.

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

KW - Acetamides

KW - Adult

KW - Brain

KW - Carbon Isotopes

KW - Dose-Response Relationship, Drug

KW - Drug Delivery Systems

KW - Female

KW - Humans

KW - Male

KW - Positron-Emission Tomography

KW - Purines

KW - Pyridines

KW - Radiography

KW - Receptors, GABA

U2 - 10.1038/jcbfm.2014.46

DO - 10.1038/jcbfm.2014.46

M3 - Article

C2 - 24643083

SN - 0271-678X

VL - 34

SP - 989

EP - 994

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

IS - 6

ER -