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 [C]PBR28, [F]DPA714 and [C]-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 [C]-R-PK11195 data from six healthy subjects. Then, we compared the [C]-R-PK11195 vascular binding estimates with previously published values for [F]DPA714 and [C]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. [C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

In vivo molecular imaging of neuroinflammation in Alzheimer's disease

“…Moreover the pharmacokinetic characteristics of [ 11 C]PBR28 seem to make it particularly challenging to model (Rizzo et al . ). Despite this, the same group has recently published a 2.7 years follow‐up study showing that (i) AD patients had a 4–6% increase in TSPO binding per annum whereas it was only 0.5–1% in HC and (ii) AD patients with the highest level and increase in TSPO binding had faster brain atrophy and cognitive decline (Kreisl et al .…”

“…However, it must be noted that [ 11 C]PBR28 has the highest differential (~40 fold) in affinity between the low and high affinity binding sites; it is therefore not suitable to image low affinity binders and will have poor sensitivity in imaging mixed-affinity binders due to the large reduction in binding due to 50% of the binding sites being low affinity. Moreover the pharmacokinetic characteristics of [ 11 C]PBR28 seem to make it particularly challenging to model (Rizzo et al 2017). Despite this, the same group has recently published a 2.7 years follow-up study showing that (i) AD patients had a 4-6% increase in TSPO binding per annum whereas it was only 0.5-1% in HC and (ii) AD patients with the highest level and increase in TSPO binding had faster brain atrophy and cognitive decline (Kreisl et al 2016).…”

Automatic Extraction of a Reference Region for the Noninvasive Quantification of Translocator Protein in Brain Using 11C-PBR28

“…Template curves such as those used for population-derived input functions may not faithfully capture individual variability, and robust estimates are obtained only when at least one blood sample is used to properly scale the template curve. Although the simultaneous estimation of the input function needs at least one blood sample, together with the time-activity curves of several brain regions (2), Schain et al estimated BP ND (binding potential) noninvasively for 11 C-PBR28 using a template input curve and demonstrated that it was able to distinguish between healthy controls and patients with Alzheimer disease (AD) (3). However, a template curve still has to be previously generated from subjects scanned with arterial sampling, and the shape of the curve obtained from a population of healthy subjects may not necessarily reflect that of pathologic conditions (3).…”

“…Indeed, it has been used in different clinical conditions associated with microglial activation (7-10). However, 11 C-(R)-PK11195 is a radioligand with low specific binding, and there seems to be an inverse relationship between the affinity of the tracer and the successful implementation of SVCA (11). Recently García-Lorenzo et al (12) showed that SVCA can also be applied to 18 F-DPA-714, a TSPO tracer with intermediate affinity for TSPO (;1.5-fold that of 11 C-(R)-PK11195 (13)).…”

“…However, 11 C-(R)-PK11195 is a radioligand with low specific binding, and there seems to be an inverse relationship between the affinity of the tracer and the successful implementation of SVCA (11). Recently García-Lorenzo et al (12) showed that SVCA can also be applied to 18 F-DPA-714, a TSPO tracer with intermediate affinity for TSPO (;1.5-fold that of 11 C-(R)-PK11195 (13)). 11 C-PBR28 is one of the most widely used TSPO tracers worldwide and has high affinity for TSPO (;5-to 6-fold that of 11 C-(R)-PK11195 (13)).…”