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

Purpose The aim of this study was to evaluate different non-invasive methods for generating (R)-1-((3-([ 11 C]methyl)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([ 11 C]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 [ 11 C]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 [ 11 C]UCB-J PET using SO as reference tissue, while reducing the dynamic acquisition to 60 min has limited impact on [ 11 C]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 [ 11 C]UCB-J BP SO parametric maps.