Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissue

PurposeA [C-11]UCB-J blocking study was performed in healthy volunteers to validate simplified, non-invasive measures for quantifying presynaptic SV2A expression using subcortical white matter as reference tissue.MethodsNinety minutes dynamic [C-11]UCB-J PET scanning with arterial blood sampling was performed in 10 healthy volunteers (8M/2F; age 27.610.0yrs), before and after administration of a novel chemical entity with selective affinity for SV2A. The centrum semi-ovale (SO) was validated as reference region by comparing baseline and post treatment distribution volume (V-T). Using SO as reference tissue, Binding Potential (BPSO) using a Simplified Reference Tissue Model (SRTM, down to 60min acquisition) and Standardized Uptake Value Ratios (60-90min post injection - SUVRSO,60-90min) were compared with regional distribution volume ratios (DVR). Next, SV2A occupancy values based on SRTM BP(SO)and SUVRSO,60-90min were compared to occupancy estimates using regional V-T values and a Lassen plot.ResultsAfter pretreatment, regional V-T values were reduced significantly except for SO. Highly significant correlations were found between DVR, SRTM BPSO and SUVRSO,60-90min. Compared to DVR, baseline SRTM BPSO showed a small bias ( 6.1%) with lower precision for shorter acquisition times, while SUVRSO,60-90min showed 3.5% bias with similar precision. Differences between SV2A occupancy values based on SUVRSO,60-90min and occupancy estimates using V-T and a Lassen plot were small but significant, while negligible bias was found for SRTM based occupancy estimates (at least 70min acquisition).Conclusion This [C-11]UCB-J blocking study validated SO as a suitable reference region for non-invasive quantification of SV2A availability and drug occupancy in the human brain. Accurate quantification can be achieved by using either SUVRSO,60-90min with a 60-90min PET acquisition or SRTM BP(SO)with at least 70min dynamic PET acquisition.