Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities

Abstract

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [¹¹C]PBR28, [¹⁸F]DPA714 and [¹¹C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [¹¹C]-R-PK11195 data from six healthy subjects. Then, we compared the [¹¹C]-R-PK11195 vascular binding estimates with previously published values for [¹⁸F]DPA714 and [¹¹C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [¹¹C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

Keywords: Translocator protein; [C]-R-PK11195; [C]PBR28; [F]DPA714; clustering; endothelium; kinetic modelling; microglia; neuroinflammation; reference region.

Figure 1.

[¹¹C]PK11195 brain PET data fit and model compartmentalization. Example of model fits to whole brain activity with standard 1- and 2-tissue modelling (a, b) and including vascular modelling with 1TCM-1K (c) and 2TCM-1K (d) in a representative healthy subject. In each panel, black circles represent the measured activity while the solid black lines represent the data model description. Single compartmental kinetics is described by blue, green and red lines, which represent non-displaceable, specific and endothelial binding, respectively. Purple solid lines represent total tissue binding (i.e. non-displaceable plus specific binding). 1TCM: one-tissue compartmental model; 2TCM: two-tissue compartmental model.

Figure 2.

Mean and variability of regional K_b estimates. TPSO vascular binding estimates (K_b) obtained from tracers with different TSPO affinity. K_b estimates (mean±SD) are shown for [¹¹C]-R-PK11195 (blue bars, n = 6), [¹⁸F]DPA714 (orange bars, n = 5) and [¹¹C]PBR28 data (grey bars, n = 18).

Figure 3.

Comparison of grey and white matter tissue kinetics. Analysis of the orthogonality of grey and white matter tissue kinetics for [¹¹C]-R-PK11195 (a), [¹⁸F]DPA714 (b) and [¹¹C]PBR28 data (c). The kinetics are reported in z-score with respect to the whole brain activity and normalized by the maximum as in supervised reference tissue clustering. z-Score normalization was calculated by subtracting from each frame its mean and dividing it by its standard deviation. White matter kinetics are displayed in the figure as the inversed curve (i.e. multiplied by −1), in order to highlight the similarity between the grey and white matter time courses.

Figure 4.

Correcting for vascular TSPO using either blood input functions or reference-based models. The 1TCM-1K and SRTM-V_b approaches for vascular binding correction are illustrated in (a) and (b), respectively. In the input function model 1TCM-1K approach, the tracer activity in the vasculature ($C_{\mathit{vasc}}$) is explicitly compartmentalized and modulated region-wise by the vascular binding rate K_b. By contrast, the SRTM-V_b approach performs a global correction of the overall tracer activity in the vasculature by extracting information on the tracer activity in both the whole blood and endothelial binding from an image-derived whole vasculature TAC ($C_B^{\mathit{IDIF}}$). Despite the differences, the two corrections provide an equivalent description of the vasculature component, because $C_B^{\mathit{IDIF}}$ corresponds to the sum of the tracer activity in the whole blood (C_b) and in the vascular compartment $C_{\mathit{vasc}}$ (c). With both approaches, V_b represents the weight of the contribution of the vascular component to the total tracer uptake in a given volume of observation (d). Although not perfectly identical (mean relative difference = −2% ± 19%), the V_b estimates are in high agreement (R = 0.8). The results refer to 1TCM-1K and SRTM-V_b, applied to the [¹¹C]PK11195 PET dataset. 1TCM: one-tissue compartmental model; PET: positron emission tomography.