Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 34, Issue 6, Pages 989-994Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2014.46
Keywords
emapunil; [C-11]PBR28; rs6971 polymorphism; specific binding; TSPO; XBD173
Categories
Funding
- MRC [G0900897, MR/L01307X/1] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL6-Owen] Funding Source: researchfish
- Medical Research Council [G0900897, MR/L01307X/1] Funding Source: researchfish
- National Institute for Health Research [CL-2011-21-002] Funding Source: researchfish
- Parkinson's UK [G-0909] Funding Source: researchfish
- Medical Research Council [MR/L01307X/1, G0900897] Funding Source: Medline
- Parkinson's UK [G-0909] Funding Source: Medline
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Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Trans locator 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 [C-11]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (V-ND), and hence estimate the BPND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [C-11]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, V-ND was estimated via the occupancy plot. Values of BPND for all subjects were calculated using this V-ND estimate. Total volume of distribution (V-T) of MABs (2.94 +/- 0.31) was lower than V-T 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 V-ND estimate of 1.98 (1.69, 2.26). Based on these V-ND estimates, BPND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [C-11]PBR28 V-ND and hence BPND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V-ND for TSPO targeting radioligands.
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