Dual time-point imaging for post-dose binding potential estimation applied to a [11C]raclopride PET dose occupancy study

Abstract

Receptor occupancy studies performed with PET often require time-consuming dynamic imaging for baseline and post-dose scans. Shorter protocol approximations based on standard uptake value ratios have been proposed. However, such methods depend on the time-point chosen for the quantification and often lead to overestimation and bias. The aim of this study was to develop a shorter protocol for the quantification of post-dose scans using a dual time-point approximation, which employs kinetic parameters from the baseline scan. Dual time-point was evaluated for a [¹¹C]raclopride PET dose occupancy study with the D2 antagonist JNJ-37822681, obtaining estimates for binding potential and receptor occupancy. Results were compared to standard simplified reference tissue model and standard uptake value ratios-based estimates. Linear regression and Bland-Altman analysis demonstrated excellent correlation and agreement between dual time-point and the standard simplified reference tissue model approach. Moreover, the stability of dual time-point-based estimates is shown to be independent of the time-point chosen for quantification. Therefore, a dual time-point imaging protocol can be applied to post-dose [¹¹C]raclopride PET scans, resulting in a significant reduction in total acquisition time while maintaining accuracy in the quantification of both the binding potential and the receptor occupancy.

Keywords: Dual time-point; [11C]raclopride; binding potential; positron emission tomography; quantification.

Figure 1.

Regression analysis of binding potential estimates. Regression analysis of BP_FD, BP_DTP and BP_SUVR with SRTM BP_ND. Identity line is shown as reference. BP_FD shows perfect correlation with SRTM BP_ND, with a R²= 1 and slope = 1 for all time frames (a). BP_DTP shows excellent correlation with SRTM BP_ND, demonstrated by a R²= 0.99 and slope = 0.99 for all time frames (b). BP_SUVR shows good correlation and a small overestimation when compared to SRTM BP_ND, presenting a R²= 0.97 and slope = 1.02 for the 20–40 min, R²= 0.98 and slope = 1.18 for the 30–50 min and R²= 0.99 and slope = 1.23 for the 40–60 min frames (c).

Figure 2.

Representation of the method’s approximation. Representative TAC for both baseline and post-dose scans of a subject with the highest occupancy levels, demonstrating the estimation of the TAC slopes by the finite differences approximation.

Figure 3.

Kinetic parameter estimation error analysis. Error analysis performed on changes in R₁ and $k_2^T$ and $k_2^R$ of up to ± 30% between baseline and post-dose scans. The percentage error in BP_DTP estimation is less than 5% for changes in R₁ (a) and less than 8% for changes in $k_2^T$ and $k_2^R$ (b).

Figure 4.

Representative noise simulations for striatal and cerebellar TACs. A representation of the noise free post-dose striatal (black) and cerebellar (gray) TACs used for the noise simulation (solid lines) together with representative TACs for the 15% noise level (dots) and their upper and lower bounds, defined as ± 1.96 × SD (dashed lines).

Figure 5.

Bland–Altman plots of receptor occupancy estimates. Representative Bland–Altman plots showing agreement between methods for estimation of receptor occupancy and the standard SRTM BP_ND based approach. The 40–60 min dual time-point interval was chosen as representative for receptor occupancy estimation using baseline SRTM BP_ND and post-dose BP_DTP (a) and baseline and postdose BP_SUVR (b).