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

[ 11 C]PBR28 is a positron emission tomography radioligand used to estimate the expression of 18kDa 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 [ 11 C]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 [ 11 C]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 [ 11 C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments showed that V ND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge showed that SIME provided VND 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 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 [ 11 C]PB28, and suggest that VS can be used in preference to, or as a complement to the conventional outcome measure V T . Additional studies in patient cohorts are warranted.