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

Purpose: A [C]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 [C]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). Using SO as reference tissue, Binding Potential (BP) using a Simplified Reference Tissue Model (SRTM, down to 60 min acquisition) and Standardized Uptake Value Ratios (60-90 min post injection - SUVR) were compared with regional distribution volume ratios (DVR). Next, SV2A occupancy values based on SRTM BP and SUVR were compared to occupancy estimates using regional V values and a Lassen plot.

Results: After pretreatment, regional V values were reduced significantly except for SO. Highly significant correlations were found between DVR, SRTM BP and SUVR. Compared to DVR, baseline SRTM BP showed a small bias (≤ 6.1%) with lower precision for shorter acquisition times, while SUVR showed 3.5% bias with similar precision. Differences between SV2A occupancy values based on SUVR and occupancy estimates using V 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 [C]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 with a 60-90 min PET acquisition or SRTM BPwith at least 70 min dynamic PET acquisition.