Nicolas Guehl

Pharmacokinetic Evaluation of the Tau PET Radiotracer 18F-T807 (18F-AV-1451) in Human Subjects

18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods: Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region–based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue. Results: The percentage of unmetabolized 18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min). 18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region–based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2 = 0.97, P < 0.0001). Conclusion: 18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80–100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.

Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.

Heat-Induced Radiolabeling of Nanoparticles for Monocyte Tracking by PET.

Heat-induced radiolabeling (HIR) yielded (89) Zr-Feraheme (FH) nanoparticles (NPs) that were used to determine NP pharmacokinetics (PK) by positron emission tomography (PET). Standard uptake values indicated a fast hepatic uptake that corresponded to blood clearance, and a second, slow uptake process by lymph nodes and spleen. By cytometry, NPs were internalized by circulating monocytes and monocytes in vitro. Using an IV injection of HIR (89) Zr-FH (rather than in vitro cell labeling), PET/PK provided a view of monocyte trafficking, a key component of the immune response.

Impact of motion and partial volume effects correction on PET myocardial perfusion imaging using simultaneous PET-MR.

PET is an established modality for myocardial perfusion imaging (MPI) which enables quantification of absolute myocardial blood flow (MBF) using dynamic imaging and kinetic modeling. However, heart motion and partial volume effects (PVE) significantly limit the spatial resolution and quantitative accuracy of PET MPI. Simultaneous PET-MR offers a solution to the motion problem in PET by enabling MR-based motion correction of PET data. The aim of this study was to develop a motion and PVE correction methodology for PET MPI using simultaneous PET-MR, and to assess its impact on both static and dynamic PET MPI using 18F-Flurpiridaz, a novel 18F-labeled perfusion tracer. Two dynamic 18F-Flurpiridaz MPI scans were performed on healthy pigs using a PET-MR scanner. Cardiac motion was tracked using a dedicated tagged-MRI (tMR) sequence. Motion fields were estimated using non-rigid registration of tMR images and used to calculate motion-dependent attenuation maps. Motion correction of PET data was achieved by incorporating tMR-based motion fields and motion-dependent attenuation coefficients into image reconstruction. Dynamic and static PET datasets were created for each scan. Each dataset was reconstructed as (i) Ungated, (ii) Gated (end-diastolic phase), and (iii) Motion-Corrected (MoCo), each without and with point spread function (PSF) modeling for PVE correction. Myocardium-to-blood concentration ratios (MBR) and apparent wall thickness were calculated to assess image quality for static MPI. For dynamic MPI, segment- and voxel-wise MBF values were estimated by non-linear fitting of a 2-tissue compartment model to tissue time-activity-curves. MoCo and Gating respectively decreased mean apparent wall thickness by 15.1% and 14.4% and increased MBR by 20.3% and 13.6% compared to Ungated images (P  <  0.01). Combined motion and PSF correction (MoCo-PSF) yielded 30.9% (15.7%) lower wall thickness and 82.2% (20.5%) higher MBR compared to Ungated data reconstructed without (with) PSF modeling (P  <  0.01). For dynamic PET, mean MBF across all segments were comparable for MoCo (0.72  ±  0.21 ml/min/ml) and Gating (0.69  ±  0.18 ml/min/ml). Ungated data yielded significantly lower mean MBF (0.59  ±  0.16 ml/min/ml). Mean MBF for MoCo-PSF was 0.80  ±  0.22 ml/min/ml, which was 37.9% (25.0%) higher than that obtained from Ungated data without (with) PSF correction (P  <  0.01). The developed methodology holds promise to improve the image quality and sensitivity of PET MPI studies performed using PET-MR.

Pseudo-reference regions for glial imaging with 11C-PBR28: investigation in two clinical cohorts

The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. Although TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudoreference approaches can minimize within-group variability and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing 2 different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received 11C-PBR28 PET scans. The occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudoreference regions by testing for the absence of group differences in SUV and distribution volume (VT) estimated with an arterial input function. The SUV from target regions (cLBP study, thalamus; ALS study, precentral gyrus) was normalized with the SUV from candidate pseudoreference regions (i.e., occipital cortex, cerebellum, and whole brain) to obtain SUVRoccip, SUVRcereb, and SUVRWB. The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without arterial input function (refDVR), and VT. Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudoreference VT or SUV, excepting whole-brain VT, which was higher in cLBP patients than controls. Target VT elevations in patients (P = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVRoccip and SUVRWB, and by refDVR and blDVR (less reliably by SUVRcereb). In voxelwise analyses, SUVRoccip, but not SUVRcereb, identified regional group differences initially observed with SUVRWB, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with VT. Although important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology-related group differences in 11C-PBR28 signal as classic kinetic modeling techniques. The occipital cortex may be a suitable pseudoreference region, at least for the populations evaluated, pending further validation in larger cohorts.

A Bayesian spatial temporal mixtures approach to kinetic parametric images in dynamic positron emission tomography.

PURPOSE Estimation of parametric maps is challenging for kinetic models in dynamic positron emission tomography. Since voxel kinetics tend to be spatially contiguous, the authors consider groups of homogeneous voxels together. The authors propose a novel algorithm to identify the groups and estimate kinetic parameters simultaneously. Uncertainty estimates for kinetic parameters are also obtained. METHODS Mixture models were used to fit the time activity curves. In order to borrow information from spatially nearby voxels, the Potts model was adopted. A spatial temporal model was built incorporating both spatial and temporal information in the data. Markov chain Monte Carlo was used to carry out parameter estimation. Evaluation and comparisons with existing methods were carried out on cardiac studies using both simulated data sets and a pig study data. One-compartment kinetic modeling was used, in which K1 is the parameter of interest, providing a measure of local perfusion. RESULTS Based on simulation experiments, the median standard deviation across all image voxels, of K1 estimates were 0, 0.13, and 0.16 for the proposed spatial mixture models (SMMs), standard curve fitting, and spatial K-means methods, respectively. The corresponding median mean squared biases for K1 were 0.04, 0.06, and 0.06 for abnormal region of interest (ROI); 0.03, 0.03, and 0.04 for normal ROI; and 0.007, 0.02, and 0.05 for the noise region. CONCLUSIONS SMM is a fully Bayesian algorithm which determines the optimal number of homogeneous voxel groups, voxel group membership, parameter estimation, and parameter uncertainty estimation simultaneously. The voxel membership can also be used for classification purposes. By borrowing information from spatially nearby voxels, SMM substantially reduces the variability of parameter estimates. In some ROIs, SMM also reduces mean squared bias.

Quantitative in vivo mapping of myocardial mitochondrial membrane potential

Background Mitochondrial membrane potential (ΔΨm) arises from normal function of the electron transport chain. Maintenance of ΔΨm within a narrow range is essential for mitochondrial function. Methods for in vivo measurement of ΔΨm do not exist. We use 18F-labeled tetraphenylphosphonium (18F-TPP+) to measure and map the total membrane potential, ΔΨT, as the sum of ΔΨm and cellular (ΔΨc) electrical potentials. Methods Eight pigs, five controls and three with a scar-like injury, were studied. Pigs were studied with a dynamic PET scanning protocol to measure 18F-TPP+ volume of distribution, VT. Fractional extracellular space (fECS) was measured in 3 pigs. We derived equations expressing ΔΨT as a function of VT and the volume-fractions of mitochondria and fECS. Seventeen segment polar maps and parametric images of ΔΨT were calculated in millivolts (mV). Results In controls, mean segmental ΔΨT = -129.4±1.4 mV (SEM). In pigs with segmental tissue injury, ΔΨT was clearly separated from control segments but variable, in the range -100 to 0 mV. The quality of ΔΨT maps was excellent, with low noise and good resolution. Measurements of ΔΨT in the left ventricle of pigs agree with previous in in-vitro measurements. Conclusions We have analyzed the factors affecting the uptake of voltage sensing tracers and developed a minimally invasive method for mapping ΔΨT in left ventricular myocardium of pigs. ΔΨT is computed in absolute units, allowing for visual and statistical comparison of individual values with normative data. These studies demonstrate the first in vivo application of quantitative mapping of total tissue membrane potential, ΔΨT.

Rapid Computation of Single PET scan Rest-Stress Myocardial Blood Flow Parametric Images by Table Look Up

Purpose We have recently reported a method for measuring rest‐stress myocardial blood flow (MBF) using a single, relatively short, PET scan session. The method requires two IV tracer injections, one to initiate rest imaging and one at peak stress. We previously validated absolute flow quantitation in ml/min/cc for standard bulls eye, segmental analysis. In this work, we extend the method for fast computation of rest‐stress MBF parametric images. Methods We provide an analytic solution to the single‐scan rest‐stress flow model which is then solved using a two‐dimensional table lookup method (LM). Simulations were performed to compare the accuracy and precision of the lookup method with the original nonlinear method (NLM). Then the method was applied to 16 single scan rest/stress measurements made in 12 pigs: seven studied after infarction of the left anterior descending artery (LAD) territory, and nine imaged in the native state. Parametric maps of rest and stress MBF as well as maps of left (fLV) and right (fRV) ventricular spill‐over fractions were generated. Regions of interest (ROIs) for 17 myocardial segments were defined in bulls eye fashion on the parametric maps. The mean of each ROI was then compared to the rest (K1r) and stress (K1s) MBF estimates obtained from fitting the 17 regional TACs with the NLM. Results In simulation, the LM performed as well as the NLM in terms of precision and accuracy. The simulation did not show that bias was introduced by the use of a predefined two‐dimensional lookup table. In experimental data, parametric maps demonstrated good statistical quality and the LM was computationally much more efficient than the original NLM. Very good agreement was obtained between the mean MBF calculated on the parametric maps for each of the 17 ROIs and the regional MBF values estimated by the NLM (K1map LM = 1.019 × K1ROI NLM + 0.019, R2 = 0.986; mean difference = 0.034 ± 0.036 mL/min/cc). Conclusions We developed a table lookup method for fast computation of parametric imaging of rest and stress MBF. Our results show the feasibility of obtaining good quality MBF maps using modest computational resources, thus demonstrating that the method can be applied in a clinical environment to obtain full quantitative MBF information.