Validation of Parametric Methods for [11C]UCB-J PET Imaging Using Subcortical White Matter as Reference Tissue

Abstract

Purpose: The aim of this study was to evaluate different non-invasive methods for generating (R)-1-((3-([¹¹C]methyl)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([¹¹C]UCB-J) parametric maps using white matter (centrum semi-ovale-SO) as reference tissue.

Procedures: Ten healthy volunteers (8 M/2F; age 27.6 ± 10.0 years) underwent a 90-min dynamic [¹¹C]UCB-J positron emission tomography (PET) scan with full arterial blood sampling and metabolite analysis before and after administration of a novel chemical entity with high affinity for presynaptic synaptic vesicle glycoprotein 2A (SV2A). A simplified reference tissue model (SRTM2), multilinear reference tissue model (MRTM2), and reference Logan graphical analysis (rLGA) were used to generate binding potential maps using SO as reference tissue (BP_SO). Shorter dynamic acquisitions down to 50 min were also considered. In addition, standard uptake value ratios (SUVR) relative to SO were evaluated for three post-injection intervals (SUVR_SO,40-70min, SUVR_SO,50-80min, and SUVR_SO,60-90min respectively). Regional parametric BP_SO + 1 and SUVR_SO were compared with regional distribution volume ratios of a 1-tissue compartment model (1TCM DVR_SO) using Spearman correlation and Bland-Altman analysis.

Results: For all methods, highly significant correlations were found between regional, parametric BP_SO + 1 (r = [0.63;0.96]) or SUVR_SO (r = [0.90;0.91]) estimates and regional 1TCM DVR_SO. For a 90-min dynamic scan, parametric SRTM2 and MRTM2 values presented similar small bias and variability (- 3.0 ± 2.9 % for baseline SRTM2) and outperformed rLGA (- 10.0 ± 5.3 % for baseline rLGA). Reducing the dynamic acquisition to 60 min had limited impact on the bias and variability of parametric SRTM2 BP_SO estimates (- 1.0 ± 9.9 % for baseline SRTM2) while a higher variability (- 1.83 ± 10.8 %) for baseline MRTM2 was observed for shorter acquisition times. Both SUVR_SO,60-90min and SUVR_SO,50-80min showed similar small bias and variability (- 2.8 ± 4.6 % bias for baseline SUVR_SO,60-90min).

Conclusion: SRTM2 is the preferred method for a voxelwise analysis of dynamic [¹¹C]UCB-J PET using SO as reference tissue, while reducing the dynamic acquisition to 60 min has limited impact on [¹¹C]UCB-J BP_SO parametric maps. For a static PET protocol, both SUVR_SO,60-90min and SUVR_SO,50-80min images are an excellent proxy for [¹¹C]UCB-J BP_SO parametric maps.

Keywords: Parametric maps; Reference tissue; Subcortical white matter; Synaptic density; [11C]UCB-J PET.