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For radioligands without a reference region, the Lassen plot can be used to estimate receptor occupancy by an exogenous drug ( O Drug ). However, the Lassen plot is not well-suited for spatial variation in O Drug . To overcome this limitation, we introduce a Lassen plot filter, i.e. a Lassen plot applied to local neighborhoods in PET images. Image data were simulated with regional variation in V N D , O Drug , both, or neither and analyzed using the change in binding potential ( Δ B P N D ), the conventional Lassen plot, and the Lassen plot filter at the region of interest (ROI) and voxel level. All methods were also applied to a human [11C]flumazenil occupancy study using PF-06372865. This combination of a non-selective radioligand and selective drug should lead to varying O Drug provided the distribution of subtypes varies spatially. In contrast with Δ B P N D and the conventional Lassen plot, ROI-level and voxel-level Lassen plot filter estimates remained unbiased in the presence of regional variation in V N D or O Drug . In the [11C]flumazenil data-set, O Drug was shown to vary regionally in accordance with the distribution of binding sites for [11C]flumazenil and PF-06372865. We demonstrate that a local-neighborhood Lassen plot filter provides robust and unbiased estimates of O Drug and V N D without the need for any user intervention. [ABSTRACT FROM AUTHOR]

Detecting fluctuations in synaptic dopamine levels in extrastriatal brain regions with [11C]FLB 457 and positron emission tomography (PET) is a valuable tool for studying dopaminergic dysfunction in psychiatric disorders. The evaluation of reference region modeling approaches would eliminate the need to obtain arterial input function data. Our goal was to explore the use of reference region models to estimate amphetamine-induced changes in [11C]FLB 457 dopamine D2/D3 binding. Six healthy tobacco smokers were imaged with [11C]FLB 457 at baseline and at 3 hours after amphetamine (0.4 to 0.5 mg/kg, per os) administration. Simplified reference tissue models, SRTM and SRTM2, were evaluated against the 2-tissue compartmental model (2TC) to estimate [11C]FLB 457 binding in extrastriatal regions of interest (ROIs), using the cerebellum as a reference region. No changes in distribution volume were observed in the cerebellum between scan conditions. SRTM and SRTM2 underestimated binding, compared with 2TC, in ROIs by 26% and 9%, respectively, with consistent bias between the baseline and postamphetamine scans. Postamphetamine, [11C]FLB 457 binding significantly decreased across several brain regions as measured with SRTM and SRTM2; no significant change was detected with 2TC. These data support the sensitivity of [11C]FLB 457 for measuring amphetamine-induced dopamine release in extrastriatal regions with SRTM and SRTM2. [ABSTRACT FROM AUTHOR]

[18F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n=5) or bolus-plus-constant-infusion (n=5) of [18F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate VT and BPND. [18F]FPEB was well fitted by the two-tissue compartment model, MA1 (t*=30), and MRTM (using cerebellum white matter as a reference). Highest VT values were observed in the anterior cingulate and caudate, and lowest VT values were observed in the cerebellum and pallidum. For kinetic modeling studies, VT and BPND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [18F]FPEB reduced intersubject variability in VT and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90-120 minutes after the start of injection. [ABSTRACT FROM AUTHOR]