Kinetic modelling of [11C]PBR28 for 18 kDa translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis

The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [11C]PBR28 and [11C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all high-affinity binders, underwent two [11C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter.

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Optimised GMP-compliant production of [18F]DPA-714 on the Trasis AllinOne module

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00133-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Klaudia A. Cybulska ◽

Vera Bloemers ◽

Lars R. Perk ◽

Peter Laverman

Keyword(s):

Significant Degree ◽

Translocator Protein ◽

Positron Emission ◽

Leaving Group ◽

Inflammatory Processes ◽

Single Production ◽

Translocator Protein 18 Kda ◽

Radiochemical Yields ◽

Specific Ligand

Abstract Background The translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [18F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [18F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity. Results [18F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [18F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100∘C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [18F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [18F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies. Conclusion To the best of our knowledge, the process presented herein is the most efficient [18F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.

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Cellular sources of TSPO expression in healthy and diseased brain

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05166-2 ◽

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.

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11C- and 18F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future

Biomedicines ◽

10.3390/biomedicines9020108 ◽

2021 ◽

Vol 9 (2) ◽

pp. 108

Author(s):

Michael R. Kilbourn

Keyword(s):

Pet Imaging ◽

In Vivo Imaging ◽

Dopamine Synthesis ◽

Dopamine System ◽

Synaptic Release ◽

Positron Emission ◽

The Central Nervous System ◽

Pet Radiotracers ◽

Selection Of

The applications of positron emission tomography (PET) imaging to study brain biochemistry, and in particular the aspects of dopamine neurotransmission, have grown significantly over the 40 years since the first successful in vivo imaging studies in humans. In vivo PET imaging of dopaminergic functions of the central nervous system (CNS) including dopamine synthesis, vesicular storage, synaptic release and receptor binding, and reuptake processes, are now routinely used for studies in neurology, psychiatry, drug abuse and addiction, and drug development. Underlying these advances in PET imaging has been the development of the unique radiotracers labeled with positron-emitting radionuclides such as carbon-11 and fluorine-18. This review focuses on a selection of the more accepted and utilized PET radiotracers currently available, with a look at their past, present and future.

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Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16650697 ◽

2016 ◽

Vol 37 (3) ◽

pp. 1095-1107 ◽

Cited By ~ 13

Author(s):

Jean-Dominique Gallezot ◽

Beata Planeta ◽

Nabeel Nabulsi ◽

Donna Palumbo ◽

Xiaoxi Li ◽

...

Keyword(s):

Binding Sites ◽

Human Subjects ◽

Receptor Occupancy ◽

Healthy Human ◽

Positron Emission ◽

Relationship Of ◽

The Relationship ◽

Pet Scans

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

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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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Glucocorticoid-induced eosinopenia results from CXCR4-dependent bone marrow migration

Blood ◽

10.1182/blood.2020005161 ◽

2020 ◽

Vol 136 (23) ◽

pp. 2667-2678

Author(s):

So Gun Hong ◽

Noriko Sato ◽

Fanny Legrand ◽

Manasi Gadkari ◽

Michelle Makiya ◽

...

Keyword(s):

Bone Marrow ◽

Rhesus Macaques ◽

Human Study ◽

Isolation Technique ◽

Selective Blockade ◽

First Line Therapy ◽

Positron Emission ◽

Before And After ◽

Eosinophilic Disorders

Abstract Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine–labeled eosinophils by serial positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies. The human study was registered at ClinicalTrials.gov as #NCT02798523.

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Noninvasive quantification of macrophagic lung recruitment during experimental ventilation-induced lung injury

Journal of Applied Physiology ◽

10.1152/japplphysiol.00825.2018 ◽

2019 ◽

Vol 127 (2) ◽

pp. 546-558

Author(s):

Laurent Bitker ◽

Nicolas Costes ◽

Didier Le Bars ◽

Franck Lavenne ◽

Maciej Orkisz ◽

...

Keyword(s):

Lung Injury ◽

Protective Ventilation ◽

Lung Recruitment ◽

Translocator Protein ◽

Emission Tomography ◽

Dynamic Strain ◽

Lung Uptake ◽

Positron Emission ◽

Ventilation Induced Lung Injury

Macrophagic lung infiltration is pivotal in the development of lung biotrauma because of ventilation-induced lung injury (VILI). We assessed the performance of [11C](R)-PK11195, a positron emission tomography (PET) radiotracer binding the translocator protein, to quantify macrophage lung recruitment during experimental VILI. Pigs ( n = 6) were mechanically ventilated under general anesthesia, using protective ventilation settings (baseline). Experimental VILI was performed by titrating tidal volume to reach a transpulmonary end-inspiratory pressure (∆PL) of 35–40 cmH2O. We acquired PET/computed tomography (CT) lung images at baseline and after 4 h of VILI. Lung macrophages were quantified in vivo by the standardized uptake value (SUV) of [11C](R)-PK11195 measured in PET on the whole lung and in six lung regions and ex vivo on lung pathology at the end of experiment. Lung mechanics were extracted from CT images to assess their association with the PET signal. ∆PL increased from 9 ± 1 cmH2O under protective ventilation, to 36 ± 6 cmH2O during experimental VILI. Compared with baseline, whole-lung [11C](R)-PK11195 SUV significantly increased from 1.8 ± 0.5 to 2.9 ± 0.5 after experimental VILI. Regional [11C](R)-PK11195 SUV was positively associated with the magnitude of macrophage recruitment in pathology ( P = 0.03). Compared with baseline, whole-lung CT-derived dynamic strain and tidal hyperinflation increased significantly after experimental VILI, from 0.6 ± 0 to 2.0 ± 0.4, and 1 ± 1 to 43 ± 19%, respectively. On multivariate analysis, both were significantly associated with regional [11C](R)-PK11195 SUV. [11C](R)-PK11195 lung uptake (a proxy of lung inflammation) was increased by experimental VILI and was associated with the magnitude of dynamic strain and tidal hyperinflation. NEW & NOTEWORTHY We assessed the performance of [11C](R)-PK11195, a translocator protein-specific positron emission tomography (PET) radiotracer, to quantify macrophage lung recruitment during experimental ventilation-induced lung injury (VILI). In this proof-of-concept study, we showed that the in vivo quantification of [11C](R)-PK11195 lung uptake in PET reflected the magnitude of macrophage lung recruitment after VILI. Furthermore, increased [11C](R)-PK11195 lung uptake was associated with harmful levels of dynamic strain and tidal hyperinflation applied to the lungs.

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Polymer-Encapsulated PC-12 Cells Demonstrate High-Affinity Uptake of Dopamine in Vitro and 18F-DOPA Uptake and Metabolism after Intracerebral Implantation in Nonhuman Primates

Cell Transplantation ◽

10.1177/096368979700600506 ◽

1997 ◽

Vol 6 (5) ◽

pp. 469-477 ◽

Cited By ~ 9

Author(s):

Thyagarajan Subramanian ◽

Dwaine F. Emerich ◽

Roy A. E. Bakay ◽

John M. Hoffman ◽

Mark M. Goodman ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Pc 12 Cells ◽

In Vivo Experiments ◽

Positron Emission ◽

Before And After ◽

Uptake And Metabolism ◽

Dopa Uptake

Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinson's disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 108 fmol/min × 106 cells, and that this uptake can be specifically blocked 88% by the addition of 10 nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP-treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5-13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer-encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinson's disease.

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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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