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Abstract: Introduction: In Positron Emission Tomography (PET) quantification of physiological parameters at the voxel level may result in unreliable estimates due to the high noise of voxel time activity curves. Global-Two-Stage (GTS), an estimation technique belonging to the group of “population approaches”, can be used to tackle this problem. GTS was previously tested on simulated PET data and yielded substantial improvements when compared to standard estimation approaches such as Weighted NonLinear Least Squares (WNLLS) and Basis Function Method (BFM). In this work GTS performance is assessed in a clinical context using the neuroinflammation marker [11C]-(R)-PK11195 applied to a cohort of Huntington''s disease (HD) patients with and without symptoms. Materials and methods: Parametric maps of binding potential (BP ND) of 12 normal controls (NC), 9 symptomatic and 9 presymptomatic HD patients were generated by applying a modified reference tissue model that accounts for tracer vascular activity in both reference and target tissues (SRTMV). GTS was then applied to SRTMV maps and its performance compared with that of SRTMV. Three smoothed versions of SRTMV, obtained by filtering the original SRTMV maps with Gaussian filters of 3mm, 5mm and 7mm Full Width Half Maximum (FWHM), were also included in the comparison. Since striatal degeneration is the hallmark of HD, sensitivity was assessed for all methods by computing the mean of z-scores in caudate, putamen and globus pallidus in the voxel-by-voxel statistical comparison of BP ND between HD and NC. Results: Application of GTS to parametric maps brought a substantial qualitative improvement to SRTMV maps to the extent that anatomical structures often became visible. In addition, most parameter estimates that were outside the physiological range with SRTMV were corrected by GTS. GTS yielded a 2.3-fold increase in sensitivity with respect to SRTMV for the symptomatic cohort (mean of striatal z-scores of 0.76 for SRTMV and 1.79 for GTS) and an even more substantial increase for the presymptomatic cohort (mean of striatal z-scores of 0.34 for SRTMV and 0.96 for GTS). The sensitivity of GTS was similar to the one obtained with a filter of 7mm FWHM applied to the initial SRTMV maps but GTS images were not characterized by the notable loss of resolution typical of smoothed maps. GTS, additionally, does not require to change/define settings according to the tracer and level of noise, whereas the choice of the FWHM value of the Gaussian filter normally employed in the smoothing procedure is typically arbitrary. Conclusions: GTS is a powerful and robust tool for improving the quality of parametric maps in PET. The method is particularly appealing in that it can be applied to any tracer and estimation method, provided that initial estimates of the parameter vector and of its covariance are available. Although the benefits of GTS are far from being exhaustively assessed, the significant improvements obtained both on real and simulated data suggest that it could become an important tool for dynamic PET in the future. [Copyright &y& Elsevier]

Introduction: Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [11C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (VND) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated. Methods: For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [11C]GR103545. Seven subjects were scanned before and 75min after oral administration of naltrexone (150mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5h and 8h after an oral dose of PF-04455242 (15mg, n=1 and 30mg, n=5). Metabolite-corrected arterial input functions were measured and all scans were 150min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (VT). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and VND. The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [11C]GR103545 in vivo KD was also estimated. Results: Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that VT was reduced in all regions; thus no suitable reference region is available for the radiotracer. VND was estimated reliably from the occupancy plot of naltrexone blocking (VND=3.4±0.9mL/cm³). The IC50 of PF-04455242 was calculated as 55ng/mL. [11C]GR103545 in vivo KD value was estimated as 0.069nmol/L. Conclusions: [11C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy. [ABSTRACT FROM AUTHOR]