Impact of Endothelial 18-kDa Translocator Protein on the Quantification of¹⁸F-DPA-714

Abstract

¹⁸F-DPA-714 is a second-generation tracer for PET imaging of the 18-kDa translocator protein (TSPO), a marker of neuroinflammation. Analysis and interpretation of TSPO PET are challenging, especially because of the basal expression of TSPO. The aim of this study was to evaluate a compartmental model that accounts for the effect of endothelial TSPO binding on the quantification of ¹⁸F-DPA-714 PET scans from a cohort of healthy subjects. <b>Methods:</b> Fifteen healthy subjects (9 high-affinity binders and 6 mixed-affinity binders) underwent ¹⁸F-DPA-714 PET scans with arterial blood sampling and metabolite analysis. The kinetic parameters were quantified using a 2-tissue compartmental model (2TC) as well as a 2TC with an extra, irreversible, compartment for endothelial binding (2TC-1K). These regional parameters and messenger RNA (mRNA) expression specific to endothelial cells were correlated with regional TSPO mRNA expression. <b>Results:</b> The 2TC-1K model was more appropriate than the 2TC for 81% of fits. The total volume of distribution was significantly reduced by 21% ± 12% across all regions with the 2TC-1K, compared with the 2TC. The endothelial binding parameter <i>K</i>_<i>b</i> varied highly across brain regions. <i>K</i>_<i>b</i> strongly and significantly correlated with all 3 probes extracted for TSPO mRNA expression (<i>r</i> = 0.80, <i>r</i> = 0.79, and <i>r</i> = 0.90), but no correlation was seen with the other binding parameters from the 2TC-1K. For the 2TC, there was a lower but significant correlation between the volume of distribution and one of the TSPO mRNA probes (<i>r</i> = 0.65). A strong, significant correlation was seen between mRNA for TSPO and genes specific to endothelial cells. <b>Conclusion:</b> Accounting for endothelial TSPO in the kinetic model improved the fit of PET data. The high correlation between <i>K</i>_<i>b</i> and TSPO mRNA suggests that the 2TC-1K model reveals more biologic information about the regional density of TSPO than the 2TC. The correlation between TSPO and endothelial cell mRNA supports the relationship between the regional variation of <i>K</i>_<i>b</i> and endothelial TSPO. These results can improve the estimation of binding parameter estimates from ¹⁸F-DPA-714 PET, especially in diseases that induce vascular change.