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 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 re- gion 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 (VT). Notably, VT reflects both specific binding (VS) and non-displaceable binding (VND). Therefore, estimates of specific binding, such as binding potentials (e.g., BPND) and specific distribution vol- ume (VS) 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 VND, which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME- derived VND, 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 showed that VND 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 VS values exhibited good reliability and precision, while larger vari- ability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [11C]PB28, and suggest that VS can be used in preference to, or as a complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.

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