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

Purpose: A [¹¹C]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.

Methods: Ninety minutes dynamic [¹¹C]UCB-J PET scanning with arterial blood sampling was performed in 10 healthy volunteers (8 M/2F; age 27.6 ± 10.0 yrs), 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 (BP_SO) using a Simplified Reference Tissue Model (SRTM, down to 60 min acquisition) and Standardized Uptake Value Ratios (60-90 min post injection - SUVR_SO,60-90min) were compared with regional distribution volume ratios (DVR). Next, SV2A occupancy values based on SRTM BP_SO and SUVR_SO,60-90min were compared to occupancy estimates using regional V_T values and a Lassen plot.

Results: After pretreatment, regional V_T values were reduced significantly except for SO. Highly significant correlations were found between DVR, SRTM BP_SO and SUVR_SO,60-90min. Compared to DVR, baseline SRTM BP_SO showed a small bias (≤ 6.1%) with lower precision for shorter acquisition times, while SUVR_SO,60-90min showed 3.5% bias with similar precision. Differences between SV2A occupancy values based on SUVR_SO,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 70 min acquisition).

Conclusion: This [¹¹C]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 SUVR_SO,60-90min with a 60-90 min PET acquisition or SRTM BP_SOwith at least 70 min dynamic PET acquisition.