Abstract
PurposePET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [11C]PK-11195 limits accurate quantification. [18F]GE-180, a novel TSPO ligand, displays superior binding to [11C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [18F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.MethodsTen volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [18F]GE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (VT) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.ResultsThe two-tissue compartment model was the best model. The average regional delivery rate constant (K1) was 0.01 mL cm−3 min−1 indicating low extraction across the blood–brain barrier (1 %). The estimated median VT across all ROIs was also low, ranging from 0.16 mL cm−3 in the striatum to 0.38 mL cm−3 in the thalamus. There were no significant differences in VT between HABs and MABs across all ROIs.ConclusionA reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low VT estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [18F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3444-z) contains supplementary material, which is available to authorized users.
Highlights
The translocator protein (TSPO) is a mitochondrial transporter involved in varied intracellular processes, but its expression in the central nervous system (CNS) is relatively low under normal physiological conditions [1]
There were no significant differences in gender, age or weight between high-affinity binders (HABs) and mixedaffinity binders (MABs)
With regard to correlations between age and the principal outcome measure, there were no significant correlations between age and volume of distribution (VT) in either HABs and MABs in any of the regions of interest (ROIs) studied (Spearman’s rho = −0.3 – 0.7 p = 0.188 – 0.873 in HABs; Spearman’s rho = 0.1 – 0.8, p = 0.104 – 0.94 in MABs)
Summary
The translocator protein (TSPO) is a mitochondrial transporter involved in varied intracellular processes, but its expression in the central nervous system (CNS) is relatively low under normal physiological conditions [1]. Activation of microglial cells caused by inflammatory stimuli results in significant upregulation of TSPO expression [2]. TSPO quantification with PET provides a measure of intrinsic neuroinflammation in a variety of CNS diseases. PET studies used the isoquinoline [11C]PK-11195 to measure TSPO. The use of [11C]PK-11195 is limited by a high nonspecific signal, making nonstandard approaches to data analysis necessary [9]. Because 11C has a half-life of 20.3 min, the use of [11C]PK-11195 is restricted to locations with an on-site cyclotron
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