A local-neighborhood Lassen plot filter for creating occupancy and non-displaceable binding images

1393 Background: Positron emission tomography (PET) can be used to estimate receptor occupancy by an exogenous drug (ODrug). For radioligands without a reference region, the Lassen plot can be used to estimate ODrug. The conventional Lassen plot provides robust single estimates for ODrug and non-displaceable binding, VND, throughout the brain. Unfortunately, this means that the Lassen plot is not well-suited for cases of spatial variation in ODrug. This limitation of the Lassen plot is of concern, since ODrug has been shown to vary spatially in the brain. To address this limitation, we introduce a “Lassen plot filter”, i.e. a Lassen plot applied at the local neighborhood level to VT images. Methods: Image data were simulated with regional variation in VND, ODrug, both, or neither. Four estimation methods were applied to simulations: the classic Lassen plot and the change in binding potential (deltaBP), as well as the Lassen plot filter at the level of an anatomical region-of-interest (ROI) and at the local neighborhood level, i.e. a 27 voxel cube. All methods were also tested on human [11C]flumazenil data-sets acquired before and after administration of a subtype-selective benzodiazepine antagonist PF-06372865. The combination of a non-selective radioligand and selective drug should lead to regionally varying ODrug provided the distribution of subtypes varies spatially. We also assessed the performance of a “univariate Lassen plot filter”, in which VND in is fixed to a brain-wide estimate. Results: Parametric ODrug and VND images were estimated with all methods. Regional variation in VND caused bias in deltaBP. Regional variation in ODrug and/or VND biased the conventional Lassen plot estimates of ODrug and VND. Regional variation in ODrug and/or VND did not bias ROI-level or voxel-level Lassen plot filter estimates. ODrug in the [11C]flumazenil data-set was shown to vary regionally in accordance with the known discrepancy between the distribution of binding sites for [11C]flumazenil and PF-06372865 (Figure). The univariate Lassen plot filter showed an expected reduction of variance in ODrug estimation, while retaining sensitivity to the spatial variation in ODrug. Conclusions: Regional variation in ODrug is known to occur, but cannot be accommodated by the conventional Lassen plot, save through manual intervention by the user. We demonstrate that a local neighborhood Lassen plot filter provides robust and unbiased estimates of ODrug and VND without the need for any user intervention. Parametric images of ODrug could be used to detect spatial variation in ODrug across the brain. This could explain unexpected selectivity of tracers or inconsistencies between whole brain ODrug and observed response to a drug. Figure Legend:ODrug and VND images created from human data based on PF-06372865 displacement of 11C-Flumazenil. The conventional Lassen plot was performed and is portrayed as images (top row). ROI-level (second row) and Voxel-level (third row) Lassen plot filters were also applied. Bottom row represent voxel-level univariate Lassen plot filter, with VND fixed to a brain-wide estimate. Color bar represents the estimated ODrug (left side) and VND (right side). The images shown are for a single subject administered 25 mg of PF-06372865.