Accuracy and reliability of [11C]PBR28 specific binding estimated without the use of a reference region

Publication date: Available online 27 November 2018

Source: NeuroImage

Author(s): Pontus Plaven-Sigray, Martin Schain, Francesca Zanderigo, Lars Farde, Christer Halldin, Anton Forsberg, Andrea Varrone, Aurelija Jucaite, Simon Cervenka, Per Stenkrona, Karin Collste, Mats Lekander, Eva Kosek, Jon Lampa, Caroline Olgart Höglund, Ilan Rabiner, Roger Gunn, Todd Ogden, Simon Cervenka

Abstract

[11C]PBR28 is a positron emission tomography radioligand used to estimate the expression of 18 kDa translocator protein (TSPO). TSPO is expressed on glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (V_T). Notably, V_T reflects both specific binding and non-displaceable binding (V_ND). Therefore, estimates of specific binding, such as binding potentials (e.g., BP_ND) and specific distribution volume (V_S) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these measures are obtainable for [11C]PBR28.

The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of V_ND, which can subsequently be used to improve the estimation of BP_ND and V_S. In this study we evaluated the accuracy of SIME-derived V_ND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans.

The simulation experiments, based on data from 54 unique [11C]PBR28 examination, showed that V_ND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided V_ND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived V_S values exhibited good reliability and precision, while larger variability was observed in SIME-derived BP_ND values.

The results support the use of SIME for quantifying specific binding of [11C]PBR28, and suggest that V_S can be used in preference to, or as a complement to the conventional outcome measure V_T. Additional studies in patient cohorts are warranted.

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