NMDA receptor ion channel activation detected in vivo with [18F]GE-179 PET after electrical stimulation of rat hippocampus

The positron emission tomography (PET) tracer [18F]GE-179 binds to the phencyclidine (PCP) site in the open N-methyl-D-aspartate receptor ion channel (NMDAR-IC). To demonstrate that PET can visualise increased [18F]GE-179 uptake by active NMDAR-ICs and that this can be blocked by the PCP antagonist S-ketamine, 15 rats had an electrode unilaterally implanted in their ventral hippocampus. Seven rats had no stimulation, five received pulsed 400 µA supra-threshold 60 Hz stimulation alone, and three received intravenous S-ketamine injection prior to stimulation. Six other rats were not implanted. Each rat had a 90 min [18F]GE-179 PET scan. Stimulated rats had simultaneous depth-EEG recordings of induced seizure activity. [18F]GE-179 uptake (volume of distribution, VT) was compared between hemispheres and between groups. Electrical stimulation induced a significant increase in [18F]GE-179 uptake at the electrode site compared to the contralateral hippocampus (mean 22% increase in VT, p = 0.0014) and to non-stimulated comparator groups. Rats injected with S-ketamine prior to stimulation maintained non-stimulated levels of [18F]GE-179 uptake during stimulation. In conclusion, PET visualisation of focal [18F]GE-179 uptake during electrically activated NMDAR-ICs and the demonstration of specificity for PCP sites by blockade with S-ketamine support the in vivo utility of [18F]GE-179 PET as a use-dependent marker of NMDAR-IC activation.

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

EJNMMI Research ◽

10.1186/s13550-021-00777-8 ◽

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.

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11C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging

Contrast Media & Molecular Imaging ◽

10.1155/2019/1760184 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Na Han ◽

Yaqun Jiang ◽

Yongkang Gai ◽

Qingyao Liu ◽

Lujie Yuan ◽

...

Keyword(s):

Breast Cancer ◽

Pik3ca Mutation ◽

Phosphatidylinositol 3 Kinase ◽

Pet Tracer ◽

Positron Emission ◽

Pet Scans ◽

Mcf 7 ◽

Phosphatidylinositol 3

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.

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Measurement of Changes in Opioid Receptor Binding in Vivo During Trigeminal Neuralgic Pain Using [11C]Diprenorphine and Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199907000-00011 ◽

1999 ◽

Vol 19 (7) ◽

pp. 803-808 ◽

Cited By ~ 64

Author(s):

Anthony K. P. Jones ◽

Niel D. Kitchen ◽

Hiroshi Watabe ◽

Vincent J. Cunningham ◽

Terry Jones ◽

...

Keyword(s):

Positron Emission Tomography ◽

Volume Of Distribution ◽

Emission Tomography ◽

Subcortical Structures ◽

Endogenous Opioid ◽

Positron Emission ◽

Before And After ◽

Pain State ◽

Parietal Cortices

The binding of [11C]diprenorphine to µ, κ, and Δ subsites in cortical and subcortical structures was measured by positron emission tomography in vivo in six patients before and after surgical relief of trigeminal neuralgia pain. The volume of distribution of [11C]diprenorphine binding was significantly increased after thermocoagulation of the relevant trigeminal division in the following areas: prefrontal, insular, perigenual, mid-cingulate and inferior parietal cortices, basal ganglia, and thalamus bilaterally. In addition to the pain relief associated with the surgical procedure, there also was an improvement in anxiety and depression scores. In the context of other studies, these changes in binding most likely resulted from the change in the pain state. The results suggest an increased occupancy by endogenous opioid peptides during trigeminal pain but cannot exclude coexistent down-regulation of binding sites.

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Kinetic Analysis of Drug–Target Interactions with PET for Characterization of Pharmacological Hysteresis

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.208 ◽

2013 ◽

Vol 33 (5) ◽

pp. 700-707 ◽

Cited By ~ 12

Author(s):

Cristian Salinas ◽

David Weinzimmer ◽

Graham Searle ◽

David Labaree ◽

Jim Ropchan ◽

...

Keyword(s):

Simulated Data ◽

Receptor Occupancy ◽

Volume Of Distribution ◽

Data Sets ◽

Suitable Model ◽

Dose Selection ◽

Care Needs ◽

Positron Emission

In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist—GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.

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Quantification of [11C]PIB PET for Imaging Myelin in the Human Brain: A Test—Retest Reproducibility Study in High-Resolution Research Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.120 ◽

2015 ◽

Vol 35 (11) ◽

pp. 1771-1782 ◽

Cited By ~ 34

Author(s):

Mattia Veronese ◽

Benedetta Bodini ◽

Daniel García-Lorenzo ◽

Marco Battaglini ◽

Salvatore Bongarzone ◽

...

Keyword(s):

High Resolution ◽

High Reliability ◽

Intraclass Correlation ◽

Volume Ratio ◽

Reference Region ◽

Brain White Matter ◽

Reproducibility Study ◽

Pet Tracer ◽

Positron Emission

An accurate in vivo measure of myelin content is essential to deepen our insight into the mechanisms underlying demyelinating and dysmyelinating neurological disorders, and to evaluate the effects of emerging remyelinating treatments. Recently [11C]PIB, a positron emission tomography (PET) tracer originally conceived as a beta-amyloid marker, has been shown to be sensitive to myelin changes in preclinical models and humans. In this work, we propose a reference-region methodology for the voxelwise quantification of brain white-matter (WM) binding for [11C]PIB. This methodology consists of a supervised procedure for the automatic extraction of a reference region and the application of the Logan graphical method to generate distribution volume ratio (DVR) maps. This approach was assessed on a test–retest group of 10 healthy volunteers using a high-resolution PET tomograph. The [11C]PIB PET tracer binding was shown to be up to 23% higher in WM compared with gray matter, depending on the image reconstruction. The DVR estimates were characterized by high reliability (outliers < 1%) and reproducibility (intraclass correlation coefficient (ICC) > 0.95). [11C]PIB parametric maps were also found to be significantly correlated ( R2 > 0.50) to mRNA expressions of the most represented proteins in the myelin sheath. On the contrary, no correlation was found between [11C]PIB imaging and nonmyelin-associated proteins.

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[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0703472104 ◽

2007 ◽

Vol 104 (23) ◽

pp. 9800-9805 ◽

Cited By ~ 210

Author(s):

H. D. Burns ◽

K. Van Laere ◽

S. Sanabria-Bohorquez ◽

T. G. Hamill ◽

G. Bormans ◽

...

Keyword(s):

Positron Emission Tomography ◽

Brain Imaging ◽

Emission Tomography ◽

Cannabinoid 1 Receptor ◽

Pet Tracer ◽

Positron Emission

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In vivo Validation of Reconstruction-Based Resolution Recovery for Human Brain Studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.225 ◽

2009 ◽

Vol 30 (2) ◽

pp. 381-389 ◽

Cited By ~ 23

Author(s):

Jurgen EM Mourik ◽

Mark Lubberink ◽

Floris HP van Velden ◽

Reina W Kloet ◽

Bart NM van Berckel ◽

...

Keyword(s):

Imaging System ◽

Volume Of Distribution ◽

Image Resolution ◽

Good Recovery ◽

Good Correspondence ◽

Resolution Recovery ◽

Positron Emission ◽

Quantitative Accuracy ◽

Spread Function

The aim of this study was to validate in vivo the accuracy of a reconstruction-based partial volume correction (PVC), which takes into account the point spread function of the imaging system. The NEMA NU2 Image Quality phantom and five healthy volunteers (using [11C]flumazenil) were scanned on both HR+ and high-resolution research tomograph (HRRT) scanners. HR+ data were reconstructed using normalization and attenuation-weighted ordered subsets expectation maximization (NAW-OSEM) and a PVC algorithm (PVC-NAW-OSEM). HRRT data were reconstructed using 3D ordinary Poisson OSEM (OP-OSEM) and a PVC algorithm (PVC-OP-OSEM). For clinical studies, parametric volume of distribution ( VT) images were generated. For phantom data, good recovery was found for both OP-OSEM (0.84 to 0.97) and PVC-OP-OSEM (0.91 to 0.98) HRRT reconstructions. In addition, for the HR+, good recovery was found for PVC-NAW-OSEM (0.84 to 0.94), corresponding well with OP-OSEM. Finally, for clinical data, good correspondence was found between PVC-NAW-OSEM and OP-OSEM-derived VT values (slope: 1.02±0.08). This study showed that HR+ image resolution using PVC-NAW-OSEM was comparable to that of the HRRT scanner. As the HRRT has a higher intrinsic resolution, this agreement validates reconstruction-based PVC as a means of improving the spatial resolution of the HR+ scanner and thereby improving the quantitative accuracy of positron emission tomography.

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A 11C-Labeled 1,4-Dihydroquinoline Derivative as a Potential PET Tracer for Imaging of Redox Status in Mouse Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.132 ◽

2015 ◽

Vol 35 (12) ◽

pp. 1930-1936 ◽

Cited By ~ 10

Author(s):

Toshimitsu Okamura ◽

Maki Okada ◽

Tatsuya Kikuchi ◽

Hidekatsu Wakizaka ◽

Ming-Rong Zhang

Keyword(s):

Mouse Brain ◽

Initial Velocity ◽

Brain Homogenate ◽

Redox Balance ◽

Redox Status ◽

Cationic Form ◽

Pet Tracer ◽

Positron Emission ◽

The Brain

A disturbance in redox balance has been implicated in the pathogenesis of a number of diseases. This study sought to examine the feasibility of imaging brain redox status using a 11C-labeled dihydroquinoline derivative ([11C]DHQ1) for positron emission tomography (PET). The lipophilic PET tracer [11C]DHQ1 was rapidly oxidized to its hydrophilic form in mouse brain homogenate. The redox modulators diphenyleneiodonium and apocynin significantly reduced the initial velocity of [11C]DHQ1 oxidation, and apocynin also caused concentration-dependent inhibition of the initial velocity. Moreover, [11C]DHQ1 readily entered the brain by diffusion after administration and underwent oxidation into the hydrophilic cationic form, which then slowly decreased. By contrast, apocynin treatment inhibited the in vivo oxidation of [11C]DHQ1 to the hydrophilic cationic form, leading to a rapid decrease of radioactivity in the brain. Thus, the difference in the [11C]DHQ1 kinetics reflects the alteration in redox status caused by apocynin. In conclusion, [11C]DHQ1 is a potential PET tracer for imaging of redox status in the living brain.

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The in Vivo Effect of Bilirubin on the N-Methyl-D-Aspartate Receptor/Ion Channel Complex in the Brains of Newborn Piglets1

Pediatric Research ◽

10.1203/00006450-199612000-00005 ◽

1996 ◽

Vol 40 (6) ◽

pp. 804-808 ◽

Cited By ~ 54

Author(s):

David J Hoffman ◽

Santina A Zanelli ◽

Joanna Kubin ◽

Om Prakash Mishra ◽

Maria Delivoria-Papadopoulos

Keyword(s):

Ion Channel ◽

Aspartate Receptor

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Synthesis and Preclinical Evaluation of [18F]PF04217903, a Selective MET PET Tracer

10.26434/chemrxiv.13095764.v1 ◽

2020 ◽

Author(s):

Vegard Torp Lien ◽

Emily Hauge ◽

Syed Nuruddin ◽

Jo Klaveness ◽

Dag Erlend Olberg

Keyword(s):

Growth Factor Receptor ◽

Radiochemical Yield ◽

Molar Activity ◽

Bioisosteric Replacement ◽

Pet Tracer ◽

Positron Emission ◽

Wide Range ◽

Hepatocyte Growth

The tyrosine kinase MET (hepatocyte growth factor receptor) is abnormally activated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (1) formed the basis for a bioisosteric replacement to the deoxyfluorinated analogue [18F]2, intended as a PET tracer for MET. [18F]2 could be synthesized with a “hydrous fluoroethylation” protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/µmol. In vitro autoradiography indicated that [18F]2 specifically binds to MET in PC3 tumor tissue, and in vivo biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs.

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