The methodology of TSPO imaging with positron emission tomography

Federico E Turkheimer, Gaia Rizzo, Peter S Bloomfield, Oliver Howes, Paolo Zanotti-Fregonara, Alessandra Bertoldo, Mattia Veronese, Federico E Turkheimer, Gaia Rizzo, Peter S Bloomfield, Oliver Howes, Paolo Zanotti-Fregonara, Alessandra Bertoldo, Mattia Veronese

Abstract

The 18-kDA translocator protein (TSPO) is consistently elevated in activated microglia of the central nervous system (CNS) in response to a variety of insults as well as neurodegenerative and psychiatric conditions. It is therefore a target of interest for molecular strategies aimed at imaging neuroinflammation in vivo. For more than 20 years, positron emission tomography (PET) has allowed the imaging of TSPO density in brain using [(11)C]-(R)-PK11195, a radiolabelled-specific antagonist of the TSPO that has demonstrated microglial activation in a large number pathological cohorts. The significant clinical interest in brain immunity as a primary or comorbid factor in illness has sparked great interest in the TSPO as a biomarker and a surprising number of second generation TSPO radiotracers have been developed aimed at improving the quality of TSPO imaging through novel radioligands with higher affinity. However, such major investment has not yet resulted in the expected improvement in image quality. We here review the main methodological aspects of TSPO PET imaging with particular attention to TSPO genetics, cellular heterogeneity of TSPO in brain tissue and TSPO distribution in blood and plasma that need to be considered in the quantification of PET data to avoid spurious results as well as ineffective development and use of these radiotracers.

Keywords: PK11195; endothelium; genetics; heterogeneity; kinetic modelling; methodology; microglia; neuroinflammation; peripheral benzodiazepine receptor (PBR); peripheral benzodiazepine receptor (PBR)28; plasma free fraction; positron emission tomography; schizophrenia; translocator protein (TSPO).

© 2015 Authors; published by Portland Press Limited.

Figures

Figure 1. Schematic representation of a standard…
Figure 1. Schematic representation of a standard dynamic PET study
The PET instrumentation allows the quantification of the concentration of the radiotracer in the organ of interest whereas additional instrumentation is used to quantify radioactive concentrations in blood. The latter is then corrected for those tracer fractions bound to red cells, platelets, plasma proteins etc., to recover the free tracer concentration in plasma. The plasma used as input function for the mathematical model that is applied to the data to obtain the parameters of interest. Kinetics curves refer to a representative [11C]-PBR28 PET study in healthy HAB.
Figure 2. Illustration of the three main…
Figure 2. Illustration of the three main factors affecting quantification of PET TSPO ligands in brain
(a) the A147T genotype, (b) the presence of abundant TSPO on the endothelium besides activated microglia and macrophages in brain tissue (Reproduced with permission from [31]: Rizzo, G., Veronese, M., Tonietto, M., Zanotti-Fregonara, P., Turkheimer, F.E. and Bertoldo, A. (2014) Kinetic modeling without accounting for the vascular component impairs the quantification of [(11)C]PBR28 brain PET data. J. Cereb. Blood Flow Metab. 34, 1060–1069 and (c) variability across human cohorts of plasma bound fractions for the tracers.
Figure 3. The effect of correcting for…
Figure 3. The effect of correcting for endothelial binding and plasma variability, two of the main factors affecting quantification of TSPO ligand, on the final end-point for the PBR28 cross-sectional study comparing schizophrenics (SCHZ, red) and matched controls (HC, blue)
The figure shows the marginal averages of the volume of distribution corrected for the A147T genotype and age for three regions (whole grey matter-GM, temporal and frontal cortex). The first row demonstrates the large variability of the results (with and without endothelial binding correction, right and left panel respectively) due to plasma variability; the reductions in the schizophrenic cohort are driven by the incorrect estimates of the free plasma concentration. Plasma variability is then taken into account by normalizing the data with whole brain uptake and results shown in the lower row. Here the incorporation of the endothelial binding in the model leads to the expected TSPO increases (right panel) whereas, without correction, end-points fluctuate erratically (left panel).

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