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8. PET imaging of GABAA receptors in pancreatic islets by [11C]flumazenil.

Author

Maloum-Rami, Faïza, Cheung, Pierre, Antoni, Gunnar, Jin, Zhe, Eriksson, Olof, and Espes, Daniel

Abstract

Background: Type 1 diabetes (T1D) is an autoimmune disease characterized by a progressive β-cell destruction. There are no clinically established methods for quantifying endocrine cells of the pancreas and current knowledge is almost exclusively based on autopsy material and functional measurements. Based on the expression of the γ-aminobutyric acid A receptors (GABAARs) in pancreatic islets and the fact that GABAAR agonists are being explored as treatment for T1D, we hypothesized that the positron emission tomography (PET) tracer [11C]flumazenil ([11C]FMZ) could serve as a marker of the endocrine mass of the pancreas. The in vivo uptake of [11C]FMZ in pig pancreas was evaluated by PET/CT, either tracer alone or after blockade of GABAAR by unlabeled flumazenil. The pancreatic binding of [11C]FMZ was investigated in vitro with frozen sections of pig pancreas as well as human organ donors, in addition to isolated mouse and human islets and exocrine preparations. The expression of GABAAR subunits in pig, human and mouse pancreas was explored by immunohistochemistry. Results: Strong specific in vivo uptake of [11C]FMZ was observed in the pig brain as expected, but in the pancreas the signal was moderate and only partially reduced by blockade. In vitro experiments revealed a positive but weak and variable binding of [11C]FMZ in islets compared to exocrine tissue in the mouse, pig and human pancreas. In pig and mouse pancreatic islets we identified the GABAAR subunits β2 and γ2 but not α2. In the human pancreas from non-diabetic donors, we have identified the α2, β2 (although weak) and γ2 subunits, whereas from a T2D donor the α2 subunit was missing. Conclusions: Our findings suggest that [11C]FMZ bind to GABAARs in the islets, but not with a sufficient contrast or magnitude to be implemented as an in vivo PET marker for the endocrine mass of the pancreas. However, GABAARs with different subunits are widely expressed in the endocrine cells within the pancreas in pig, human and mouse. Hence, the GABAAR could still be a potential imaging target for the endocrine cells of the pancreas but would require tracers with higher affinity and selectivity for individual GABAAR subunits. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study

Author

Wechalekar, Ashutosh, Antoni, Gunnar, Al Azzam, Wasfi, Bergström, Mats, Biswas, Swethajit, Chen, Chao, Cheriyan, Joseph, Cleveland, Matthew, Cookson, Louise, Galette, Paul, Janiczek, Robert L., Kwong, Raymond Y., Lukas, Mary Ann, Millns, Helen, Richards, Duncan, Schneider, Ian, Solomon, Scott D., Sörensen, Jens, Storey, James, Thompson, Douglas, van Dongen, Guus, Vugts, Danielle J., Wall, Anders, Wikström, Gerhard, and Falk, Rodney H.

Published
2022
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16. Automated radiosynthesis of [18F]CETO, a PET radiotracer for imaging adrenal glands, on Synthra RNplus

Author

Hird, Matthew, Russell, Joseph J., Li Corrigan, Lei, Boros, Istvan, Nordeman, Patrik, Antoni, Gunnar, Gurnell, Mark, Aigbirhio, Franklin I., Hird, Matthew, Russell, Joseph J., Li Corrigan, Lei, Boros, Istvan, Nordeman, Patrik, Antoni, Gunnar, Gurnell, Mark, and Aigbirhio, Franklin I.

Abstract

Primary aldosteronism (PA) is the leading secondary cause of hypertension. Determining whether one (unilateral) or both (bilateral) adrenal glands are the source of PA in a patient remains challenging, and yet it is a critical step in the decision whether to recommend potentially curative surgery (adrenalectomy) or lifelong medical therapy (typically requiring multiple drugs). Recently, we have developed a fluorine-18 radiopharmaceutical [(18) F]CETO to permit greater access to PA molecular imaging. Herein, we report an automated synthesis of this radiotracer. To manufacture the radiopharmaceutical routinely for clinical PET studies, we implemented an automated radiosynthesis method on a Synthra RNplus (c) synthesiser for which Cl-tosyletomidate was used as the precursor for radiolabelling via nucleophilic [(18) F]fluorination. [(18) F]CETO was produced with 35 +/- 1% (n = 7), decay corrected and 25 +/- 4% (n = 7) non-decay corrected radiochemical yield with molar activities ranging from 150 to 400 GBq/mu mol. The GMP compliant manufacturing process produces a sterile formulated [(18) F]CETO injectable solution for human use as demonstrated by the results of quality control. Automation of the radiosynthesis of [(18) F]CETO should facilitate uptake by other adrenal centres and increase access to molecular imaging in PA.

Published
2024
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23. Evaluation of [11C]UCB-A positron emission tomography in human brains.

Author

Xiong, Mengfei, Lubberink, Mark, Appel, Lieuwe, Fang, Xiaotian Tsong, Danfors, Torsten, Kumlien, Eva, and Antoni, Gunnar

Subjects
POSITRON emission tomography, BRAIN tomography, RADIOACTIVE tracers, GRAY matter (Nerve tissue), SYNAPTIC vesicles
Abstract

Background: In preclinical studies, the positron emission tomography (PET) imaging with [11C]UCB-A provided promising results for imaging synaptic vesicle protein 2A (SV2A) as a proxy for synaptic density. This paper reports the first-in-human [11C]UCB-A PET study to characterise its kinetics in healthy subjects and further evaluate SV2A-specific binding. Results: Twelve healthy subjects underwent 90-min baseline [11C]UCB-A scans with PET/MRI, with two subjects participating in an additional blocking scan with the same scanning procedure after a single dose of levetiracetam (1500 mg). Our results indicated abundant [11C]UCB-A brain uptake across all cortical regions, with slow elimination. Kinetic modelling of [11C]UCB-A PET using various compartment models suggested that the irreversible two-tissue compartment model best describes the kinetics of the radioactive tracer. Accordingly, the Patlak graphical analysis was used to simplify the analysis. The estimated SV2A occupancy determined by the Lassen plot was around 66%. Significant specific binding at baseline and comparable binding reduction as grey matter precludes the use of centrum semiovale as reference tissue. Conclusions: [11C]UCB-A PET imaging enables quantifying SV2A in vivo. However, its slow kinetics require a long scan duration, which is impractical with the short half-life of carbon-11. Consequently, the slow kinetics and complicated quantification methods may restrict its use in humans. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Radiation dosimetry of para-chloro-2-[18F]fluoroethyl-etomidate: a PET tracer for adrenocortical imaging.

Author

Silins, Isabella, Moreno, Adrian, Wall, Anders, Aigbirhio, Franklin, Gurnell, Mark, Brown, Morris, Roslin, Sara, Antoni, Gunnar, Hellman, Per, Sundin, Anders, and Lubberink, Mark

Subjects
RADIATION dosimetry, ADRENAL glands, POSITRON emission tomography, ABSORBED dose, METHYL formate, THERMOLUMINESCENCE dosimetry
Abstract

Background: [11C]metomidate, a methyl ester analogue of etomidate, is used for positron emission tomography of adrenocortical cancer, and has been tested in recent clinical trials for lateralization in primary aldosteronism (PA). However, in PA, visualization as well as uptake quantification are hampered by the tracer's rather high non-specific liver uptake, and its overall clinical usefulness is also limited by the short 20-minute half-life of carbon-11. Therefore, we evaluated para-chloro-2-[18F]fluoroethyl-etomidate, [18F]CETO, a fluorine-18 (T1/2=109.8 min) analogue, as a potential new adrenocortical PET tracer. The aim of this study was to assess radiation dosimetry of [18F]CETO. Results: [18F]CETO showed a high uptake in adrenal glands, still increasing at 5 h post injection. Adrenal glands (absorbed dose coefficients 0.100 ± 0.032 mGy/MBq in males and 0.124 ± 0.013 mGy/MBq in females) received the highest absorbed dose. The effective dose coefficient was 20 µSv/MBq. Conclusions: [18F]CETO has a favourable biodistribution in humans for adrenal imaging. The effective dose for a typical clinical PET examination with 200 MBq [18F]CETO is 4 mSv. Trial registration: ClinicalTrials.gov, NCT05361083 Retrospectively registered 29 April 2022. at, URL: https://clinicaltrials.gov/ct2/show/NCT05361083. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Non-invasive imaging of neutrophils in acute sepsis

Author

Wilske, Frida, primary, Eriksson, Olof, additional, Sigfridsson, Jonathan, additional, Janols, Helena, additional, Skorup, Paul, additional, Khalil, Amina, additional, Roslin, Sara, additional, Lipcsey, Miklos, additional, Castegren, Markus, additional, and Antoni, Gunnar, additional

Published
2023
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37. Automated radiosynthesis of [18F]CETO, a PET radiotracer for imaging adrenal glands, on Synthra RNplus.

Author

Hird, Matthew, Russell, Joseph J., Corrigan, Lei Li, Boros, Istvan, Nordeman, Patrik, Antoni, Gunnar, Gurnell, Mark, and Aigbirhio, Franklin I.

Subjects
POSITRON emission tomography, ADRENAL glands, MANUFACTURING processes, RADIOPHARMACEUTICALS, QUALITY control, RADIOLABELING
Abstract

Primary aldosteronism (PA) is the leading secondary cause of hypertension. Determining whether one (unilateral) or both (bilateral) adrenal glands are the source of PA in a patient remains challenging, and yet it is a critical step in the decision whether to recommend potentially curative surgery (adrenalectomy) or lifelong medical therapy (typically requiring multiple drugs). Recently, we have developed a fluorine‐18 radiopharmaceutical [18F]CETO to permit greater access to PA molecular imaging. Herein, we report an automated synthesis of this radiotracer. To manufacture the radiopharmaceutical routinely for clinical PET studies, we implemented an automated radiosynthesis method on a Synthra RNplus© synthesiser for which Cl‐tosyletomidate was used as the precursor for radiolabelling via nucleophilic [18F]fluorination. [18F]CETO was produced with 35 ± 1% (n = 7), decay corrected and 25 ± 4% (n = 7) non‐decay corrected radiochemical yield with molar activities ranging from 150 to 400 GBq/μmol. The GMP compliant manufacturing process produces a sterile formulated [18F]CETO injectable solution for human use as demonstrated by the results of quality control. Automation of the radiosynthesis of [18F]CETO should facilitate uptake by other adrenal centres and increase access to molecular imaging in PA. [ABSTRACT FROM AUTHOR]

Published
2024
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40. In Vivo Visualization and Quantification of Neutrophil Elastase in Lungs of COVID-19 Patients : A First-in-Humans PET Study with 11C-NES

Author

Antoni, Gunnar, Lubberink, Mark, Sörensen, Jens, Lindström, Elin, Elgland, Mathias, Eriksson, Olof, Hultström, Michael, Frithiof, Robert, Wanhainen, Anders, Sigfridsson, Jonathan, Skorup, Paul, Lipcsey, Miklos, Antoni, Gunnar, Lubberink, Mark, Sörensen, Jens, Lindström, Elin, Elgland, Mathias, Eriksson, Olof, Hultström, Michael, Frithiof, Robert, Wanhainen, Anders, Sigfridsson, Jonathan, Skorup, Paul, and Lipcsey, Miklos

Abstract

COVID-19 can cause life-threatening lung-inflammation that is suggested to be mediated by neutrophils, whose effector mechanisms in COVID-19 is inexplicit. The aim of the present work is to evaluate a novel PET tracer for neutrophil elastase in COVID-19 patients and healthy controls. METHODS: In this open-label, First-In-Man study, four patients with hypoxia due to COVID-19 and two healthy controls were investigated with positron emission tomography (PET) using the new selective and specific neutrophil elastase PET-tracer [11C]GW457427 and [15O]water for the visualization and quantification of NE and perfusion in the lungs, respectively. RESULTS: [11C]GW457427 accumulated selectively in lung areas with ground-glass opacities on computed tomography characteristic of COVID-19 suggesting high levels on NE in these areas. In the same areas perfusion was severely reduced in comparison to healthy lung tissue as measured with [15O]water. CONCLUSION: The data suggests that NE may be responsible for the severe lung inflammation in COVID-19 patients and that inhibition of NE could potentially reduce the acute inflammatory process and improve the condition., De två sista författarna delar sistaförfattarskapet

Published
2023
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41. PET imaging of neutrophil elastase with 11C-GW457427 in Acute Respiratory Distress Syndrome in pigs

Author

Puuvuori, Emmi, Chiodaroli, Elena, Estrada, Sergio, Cheung, Pierre, Lubenow, Norbert, Sigfridsson, Jonathan, Romelin, Hampus, Ingvast, Sofie, Elgland, Mathias, Liggieri, Francesco, Korsgren, Olle, Perchiazzi, Gaetano, Eriksson, Olof, Antoni, Gunnar, Puuvuori, Emmi, Chiodaroli, Elena, Estrada, Sergio, Cheung, Pierre, Lubenow, Norbert, Sigfridsson, Jonathan, Romelin, Hampus, Ingvast, Sofie, Elgland, Mathias, Liggieri, Francesco, Korsgren, Olle, Perchiazzi, Gaetano, Eriksson, Olof, and Antoni, Gunnar

Abstract

Today, there is a lack of clinically available imaging techniques to detect and quantify specific immune cell populations. Neutrophils are one of the first immune cells at the site of inflammation, and they secrete the serine protease neutrophil elastase (NE), which is crucial in the fight against pathogens. However, the prolonged lifespan of neutrophils increases the risk that patients will develop severe complications, such as acute respiratory distress syndrome (ARDS). Here, we evaluated the novel radiolabeled NE inhibitor 11C-GW457427 in a pig model of ARDS, for detection and quantification of neutrophil activity in the lungs. Methods: ARDS was induced by intravenous administration of oleic acid to 5 farm pigs, and 4 were considered healthy controls. The severity of ARDS was monitored by clinical parameters of lung function and plasma biomarkers. Each pig was studied with 11C-GW457427 and PET/CT, before and after pretreatment with the NE inhibitor GW311616 to determine in vivo binding specificity. PET image data were analyzed as SUVs and correlated with immunohistochemical staining for NE in biopsies. Results: The binding of 11C-GW457427 was increased in pig lungs with induced ARDS (median SUVmean, 1.91; interquartile range [IQR], 1.67-2.55) compared with healthy control pigs (P < 0.05 and P = 0.03, respectively; median SUVmean, 1.04; IQR, 0.66-1.47). The binding was especially strong in lung regions with high levels of NE and ongoing inflammation, as verified by immunohisto-chemistry. The binding was successfully blocked by pretreatment of an NE inhibitor drug, which demonstrated the in vivo specificity of 11C-GW457427 (P < 0.05 and P = 0.04, respectively; median SUVmean, 0.60; IQR, 0.58-0.77). The binding in neutrophil-rich tissues such as bone marrow (P < 0.05 and P = 0.04, respectively; baseline median SUVmean, 5.01; IQR, 4.48-5.49; block median SUVmean, 1.57; IQR, 0.95-1.85) and spleen (median SUVmean, 2.14; IQR, 1.19-2.36) was also high in all pig

Published
2023
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