scholarly journals The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sébastien Goutal ◽  
Martine Guillermier ◽  
Guillaume Becker ◽  
Mylène Gaudin ◽  
Yann Bramoullé ◽  
...  
Keyword(s):  
Slow Component ◽  
Specific Binding ◽  
Compartment Model ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Pharmacokinetic Data ◽  
Limited Information ◽  
Positron Emission ◽  
Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

scholarly journals The Pharmacokinetics of [18F]UCB-H Revisited in The Healthy Non-Human Primate Brain

2020 ◽  
Author(s):  
Sébastien Goutal ◽  
Martine Guillermier ◽  
Guillaume Becker ◽  
Mylène Gaudin ◽  
Yann Bramoullé ◽  
...  
Keyword(s):  
Slow Component ◽  
Specific Binding ◽  
Compartment Model ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Pharmacokinetic Data ◽  
Limited Information ◽  
Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we aimed to characterize [18F]UCB-H in the non-human cynomolgus primate and to discuss the obtained results in the light of the current state of SV2A PET ligands.Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), even though a slow component led to instability for the estimation of k3 and k4, and hence the total volume of distribution. 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower non-displaceable binding potential, BPND (estimated by k3/k4), of [18F]UCB-H compared to the newest SV2A-ligands. However, the non-displaceable distribution volume (VND) and the influx parameter (K1) is similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50 % displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

scholarly journals In vivo evidence for dysregulation of mGluR5 as a biomarker of suicidal ideation

2019 ◽  
Vol 116 (23) ◽  
pp. 11490-11495 ◽  
Author(s):  
Margaret T. Davis ◽  
Ansel Hillmer ◽  
Sophie E. Holmes ◽  
Robert H. Pietrzak ◽  
Nicole DellaGioia ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Suicide Risk ◽  
Potential Role ◽  
Input Function ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Regions Of Interest ◽  
Emission Tomography ◽  
Positron Emission

Recent evidence implicates dysregulation of metabotropic glutamatergic receptor 5 (mGluR5) in pathophysiology of PTSD and suicidality. Using positron emission tomography and [18F]FPEB, we quantified mGluR5 availability in vivo in individuals with PTSD (n = 29) and MDD (n = 29) as a function of suicidal ideation (SI) to compare with that of healthy comparison controls (HC; n = 29). Volume of distribution was computed using a venous input function in the five key frontal and limbic brain regions. We observed significantly higher mGluR5 availability in PTSD compared with HC individuals in all regions of interest (P’s = 0.001–0.01) and compared with MDD individuals in three regions (P’s = 0.007). mGluR5 availability was not significantly different between MDD and HC individuals (P = 0.17). Importantly, we observed an up-regulation in mGluR5 availability in the PTSD-SI group (P’s = 0.001–0.007) compared with PTSD individuals without SI. Findings point to the potential role for mGluR5 as a target for intervention and, potentially, suicide risk management in PTSD.

scholarly journals Kinetic Modeling of [11C]Raclopride: Combined PET-Microdialysis Studies

1997 ◽  
Vol 17 (9) ◽  
pp. 932-942 ◽  
Author(s):  
Christopher J. Endres ◽  
Bhaskar S. Kolachana ◽  
Richard C. Saunders ◽  
Tom Su ◽  
Daniel Weinberger ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Specific Binding ◽  
Compartment Model ◽  
Emission Tomography ◽  
Extended Model ◽  
Simulation Studies ◽  
Time Activity ◽  
Endogenous Dopamine ◽  
Positron Emission

The in vivo binding of D2 receptor ligands can be affected by agents that alter the concentration of endogenous dopamine. To define a more explicit relation between dopamine and D2 receptor binding, the conventional compartment model for reversible ligands has been extended to account for a time-varying dopamine pulse. This model was tested with [11C]raclopride positron emission tomography and dopamine microdialysis data that were acquired simultaneously in rhesus monkeys. The microdialysis data were incorporated into the model assuming a proportional relation to synaptic dopamine. Positron emission tomography studies used a bolus-plus-infusion tracer delivery with amphetamine given at 40 minutes to induce dopamine release. The extended model described the entire striatal time–activity curve, including the decrease in radioactivity concentration after an amphetamine-induced dopamine pulse. Based on these results, simulation studies were performed using the extended model. The simulation studies showed that the percent decrease in specific binding after amphetamine measured with the bolus-plus-infusion protocol correlates well with the integral of the postamphetamine dopamine pulse. This suggests that changes in specific binding observed in studies in humans can be interpreted as being linearly proportional to the integral of the amphetamine-induced dopamine pulse.

scholarly journals Parametric methods for [18F]flortaucipir PET

2018 ◽  
Vol 40 (2) ◽  
pp. 365-373 ◽  
Author(s):  
Sandeep SV Golla ◽  
Emma E Wolters ◽  
Tessa Timmers ◽  
Rik Ossenkoppele ◽  
Chris WJ van der Weijden ◽  
...  
Keyword(s):  
Specific Binding ◽  
Volume Ratio ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Distribution Volume ◽  
Binding Potential ◽  
Parametric Images ◽  
Distribution Volume Ratio ◽  
Pet Scans

[18F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer’s disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [18F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BPND) and volume of distribution (VT) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_VB). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BPND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) ( r2 = 0.92; slope = 0.99) derived VT correlated well with NLR-derived VT. RPM ( r2 = 0.95; slope = 0.98) derived BPND correlated well with NLR-derived DVR. Although SUVr80–100 min correlated well with NLR-derived DVR ( r2 = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.

scholarly journals The P2X7 receptor tracer [11C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study

2019 ◽  
Vol 47 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Marloes H. J. Hagens ◽  
Sandeep S. V. Golla ◽  
Bieneke Janssen ◽  
Danielle J. Vugts ◽  
Wissam Beaino ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Specific Binding ◽  
Compartment Model ◽  
Brain Regions ◽  
Binding Potential ◽  
Healthy Controls ◽  
Time Activity ◽  
Tissue Compartment ◽  
Pet Tracer

Abstract Purpose The novel PET tracer [11C]SMW139 binds with high affinity to the P2X7 receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [11C]SMW139 in patients with active relapsing remitting multiple sclerosis (RRMS) and healthy controls (HC) and to evaluate its potential to identify in vivo neuroinflammation in RRMS. Methods Five RRMS patients and 5 age-matched HC underwent 90-min dynamic [11C]SMW139 PET scans, with online continuous and manual arterial sampling to generate a metabolite-corrected arterial plasma input function. Tissue time activity curves were fitted to single- and two-tissue compartment models, and the model that provided the best fits was determined using the Akaike information criterion. Results The optimal model for describing [11C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k4 fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (VT) and binding potential (BPND) in RRMS compared with HC in normal appearing brain regions. BPND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased VT was observed in enhancing lesions, possibly resulting from disruption of the blood-brain barrier in active MS lesions. In addition, there was a high correlation between parameters obtained from 60- to 90-min datasets, although analyses using 60-min data led to a slight underestimation in regional VT and BPND values. Conclusions This first in-man study demonstrated that uptake of [11C]SMW139 can be quantified with PET using BPND as a measure for specific binding in healthy controls and RRMS patients. Additional studies are warranted for further clinical evaluation of this novel neuroinflammation tracer.

scholarly journals In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences

2021 ◽  
pp. 0271678X2098150
Author(s):  
June van Aalst ◽  
Jenny Ceccarini ◽  
Stefan Sunaert ◽  
Patrick Dupont ◽  
Michel Koole ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Medial Temporal Lobe ◽  
Regional Differences ◽  
Specific Binding ◽  
Aerobic Glycolysis ◽  
Glucose Consumption ◽  
Brain Regions ◽  
Synaptic Density ◽  
Energy Demands

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [11C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [18F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [11C]UCB-J were indeed highly significantly correlated ( r > 0.47, p < 0.001). However, regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed, with up to 19% higher [11C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

scholarly journals Cellular sources of TSPO expression in healthy and diseased brain

2021 ◽  
Author(s):  
Erik Nutma ◽  
Kelly Ceyzériat ◽  
Sandra Amor ◽  
Stergios Tsartsalis ◽  
Philippe Millet ◽  
...  
Keyword(s):  
Cell Activity ◽  
Brain Regions ◽  
Cellular Level ◽  
Translocator Protein ◽  
Disease Stage ◽  
Animal Models Of Disease ◽  
Positron Emission ◽  
Neuropsychiatric Diseases ◽  
Tspo Expression

AbstractThe 18 kDa translocator protein (TSPO) is a highly conserved protein located in the outer mitochondrial membrane. TSPO binding, as measured with positron emission tomography (PET), is considered an in vivo marker of neuroinflammation. Indeed, TSPO expression is altered in neurodegenerative, neuroinflammatory, and neuropsychiatric diseases. In PET studies, the TSPO signal is often viewed as a marker of microglial cell activity. However, there is little evidence in support of a microglia-specific TSPO expression. This review describes the cellular sources and functions of TSPO in animal models of disease and human studies, in health, and in central nervous system diseases. A discussion of methods of analysis and of quantification of TSPO is also presented. Overall, it appears that the alterations of TSPO binding, their cellular underpinnings, and the functional significance of such alterations depend on many factors, notably the pathology or the animal model under study, the disease stage, and the involved brain regions. Thus, further studies are needed to fully determine how changes in TSPO binding occur at the cellular level with the ultimate goal of revealing potential therapeutic pathways.

scholarly journals Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

2021 ◽  
Vol 22 (5) ◽  
pp. 2285
Author(s):  
Thu Hang Lai ◽  
Susann Schröder ◽  
Magali Toussaint ◽  
Sladjana Dukić-Stefanović ◽  
Mathias Kranz ◽  
...  
Keyword(s):  
Specific Binding ◽  
Brain Slices ◽  
Total Activity ◽  
Biological Evaluation ◽  
Adenosine A2a Receptor ◽  
Positron Emission ◽  
A2a Receptor ◽  
Adenosine A2a

The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

Determination of cerebral glucose transport and metabolic kinetics by dynamic MR spectroscopy

1997 ◽  
Vol 273 (6) ◽  
pp. E1216-E1227 ◽  
Author(s):  
P. C. M. Van Zijl ◽  
D. Davis ◽  
S. M. Eleff ◽  
C. T. W. Moonen ◽  
R. J. Parker ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Kinetic Equations ◽  
Direct Determination ◽  
Life Time ◽  
Compartment Model ◽  
Brain Extract ◽  
Influx Rate ◽  
Positron Emission

A new in vivo nuclear magnetic resonance (NMR) spectroscopy method is introduced that dynamically measures cerebral utilization of magnetically labeled [1-13C]glucose from the change in total brain glucose signals on infusion. Kinetic equations are derived using a four-compartment model incorporating glucose transport and phosphorylation. Brain extract data show that the glucose 6-phosphate concentration is negligible relative to glucose, simplifying the kinetics to three compartments and allowing direct determination of the glucose-utilization half-life time [ t ½ = ln2/( k 2 + k 3)] from the time dependence of the NMR signal. Results on isofluorane ( n = 5)- and halothane ( n = 7)- anesthetized cats give a hyperglycemic t ½ = 5.10 ± 0.11 min−1 (SE). Using Michaelis-Menten kinetics and an assumed half-saturation constant Kt = 5 ± 1 mM, we determined a maximal transport rate T max = 0.83 ± 0.19 μmol ⋅ g−1 ⋅ min−1, a cerebral metabolic rate of glucose CMRGlc = 0.22 ± 0.03 μmol ⋅ g−1 ⋅ min−1, and a normoglycemic cerebral influx rate CIRGlc = 0.37 ± 0.05 μmol ⋅ g−1 ⋅ min−1. Possible extension of this approach to positron emission tomography and proton NMR is discussed.

scholarly journals Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

2011 ◽  
Vol 32 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Federico E Turkheimer ◽  
Sudhakar Selvaraj ◽  
Rainer Hinz ◽  
Venkatesha Murthy ◽  
Zubin Bhagwagar ◽  
...  
Keyword(s):  
Specific Binding ◽  
Normal Subjects ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Accurate Estimation ◽  
Data Sets ◽  
Reference Region ◽  
Reference Tissue ◽  
Positron Emission ◽  
Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

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