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

[¹¹C]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in 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. Therefore, estimates of specific binding, such as binding potential (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 outcome 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 the non-displaceable distribution volume (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 examinations, 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 complement to the conventional outcome measure V_T. Additional studies in patient cohorts are warranted.