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7. Preclinical evaluation of the novel [18F]CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington's disease.

Author

Zajicek, Franziska, Verhaeghe, Jeroen, De Lombaerde, Stef, Van Eetveldt, Annemie, Miranda, Alan, Munoz-Sanjuan, Ignacio, Dominguez, Celia, Khetarpal, Vinod, Bard, Jonathan, Liu, Longbin, Staelens, Steven, and Bertoglio, Daniele

Subjects
HUNTINGTON disease, POSITRON emission tomography, AUTORADIOGRAPHY, LABORATORY mice, RADIOACTIVE tracers, ANIMAL disease models
Abstract

Purpose: Positron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington's disease (HD). To date, the focus has been mainly on the investigation of 11C radioligands; however, favourable 18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD. Methods: After characterising [18F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand. Results: Plasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [18F]CHDI-650. Both in vitro autoradiography and in vivo [18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p < 0.0001) despite the poor test–retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R. Conclusion: Overall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable 18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Unravelling and Exploiting Astrocyte Dysfunction in Huntington’s Disease

Author

Khakh, Baljit S, Beaumont, Vahri, Cachope, Roger, Munoz-Sanjuan, Ignacio, Goldman, Steven A, and Grantyn, Rosemarie

Subjects
Brain Disorders, Neurosciences, Rare Diseases, Huntington's Disease, Neurodegenerative, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Aetiology, Neurological, Animals, Astrocytes, Humans, Huntington Disease, EAAT2, GAT3, GCaMP, GLT1, HD, KCNJ10, Kir4.1, astrocyte, calcium, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Astrocytes are abundant within mature neural circuits and are involved in brain disorders. Here, we summarize our current understanding of astrocytes and Huntington's disease (HD), with a focus on correlative and causative dysfunctions of ion homeostasis, calcium signaling, and neurotransmitter clearance, as well as on the use of transplanted astrocytes to produce therapeutic benefit in mouse models of HD. Overall, the data suggest that astrocyte dysfunction is an important contributor to the onset and progression of some HD symptoms in mice. Additional exploration of astrocytes in HD mouse models and humans is needed and may provide new therapeutic opportunities to explore in conjunction with neuronal rescue and repair strategies.

Published
2017

10. Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction

Author

Colarusso, Stefania, De Simone, Daniele, Frattarelli, Tommaso, Andreini, Matteo, Cerretani, Mauro, Missineo, Antonino, Moretti, Daniele, Tambone, Sara, Kempf, Georg, Augustin, Martin, Steinbacher, Stefan, Munoz-Sanjuan, Ignacio, Park, Larry, Summa, Vincenzo, Tomei, Licia, Bresciani, Alberto, Dominguez, Celia, Toledo-Sherman, Leticia, and Bianchi, Elisabetta

Published
2020
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16. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) drug discovery: Biochemical toolbox to develop NRF2 activators by reversible binding of Kelch-like ECH-associated protein 1 (KEAP1)

Author

Bresciani, Alberto, Missineo, Antonino, Gallo, Mariana, Cerretani, Mauro, Fezzardi, Paola, Tomei, Licia, Cicero, Daniel Oscar, Altamura, Sergio, Santoprete, Alessia, Ingenito, Raffaele, Bianchi, Elisabetta, Pacifici, Robert, Dominguez, Celia, Munoz-Sanjuan, Ignacio, Harper, Steven, Toledo-Sherman, Leticia, and Park, Larry C.

Published
2017
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18. In Vivo Cerebral Imaging of Mutant Huntingtin Aggregates Using11C-CHDI-180R PET in a Nonhuman Primate Model of Huntington Disease

Author

Bertoglio, Daniele, primary, Weiss, Alison R., additional, Liguore, William, additional, Martin, Lauren Drew, additional, Hobbs, Theodore, additional, Templon, John, additional, Srinivasan, Sathya, additional, Dominguez, Celia, additional, Munoz-Sanjuan, Ignacio, additional, Khetarpal, Vinod, additional, Verhaeghe, Jeroen, additional, Staelens, Steven, additional, Link, Jeanne, additional, Liu, Longbin, additional, Bard, Jonathan A., additional, and McBride, Jodi L., additional

Published
2023
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20. Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington’s Disease Models

Author

Beaumont, Vahri, Zhong, Sheng, Lin, Hai, Xu, WenJin, Bradaia, Amyaouch, Steidl, Esther, Gleyzes, Melanie, Wadel, Kristian, Buisson, Bruno, Padovan-Neto, Fernando E., Chakroborty, Shreaya, Ward, Karen M., Harms, John F., Beltran, Jose, Kwan, Mei, Ghavami, Afshin, Häggkvist, Jenny, Tóth, Miklós, Halldin, Christer, Varrone, Andrea, Schaab, Christoph, Dybowski, J. Nikolaj, Elschenbroich, Sarah, Lehtimäki, Kimmo, Heikkinen, Taneli, Park, Larry, Rosinski, James, Mrzljak, Ladislav, Lavery, Daniel, West, Anthony R., Schmidt, Christopher J., Zaleska, Margaret M., and Munoz-Sanjuan, Ignacio

Published
2016
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21. The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

Author

Beaumont, Vahri, Mrzljak, Ladislav, Dijkman, Ulrike, Freije, Robert, Heins, Mariette, Rassoulpour, Arash, Tombaugh, Geoffrey, Gelman, Simon, Bradaia, Amyaouch, Steidl, Esther, Gleyzes, Melanie, Heikkinen, Taneli, Lehtimäki, Kimmo, Puoliväli, Jukka, Kontkanen, Outi, Javier, Robyn M., Neagoe, Ioana, Deisemann, Heike, Winkler, Dirk, Ebneth, Andreas, Khetarpal, Vinod, Toledo-Sherman, Leticia, Dominguez, Celia, Park, Larry C., and Munoz-Sanjuan, Ignacio

Published
2016
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22. Therapeutic Strategies for Huntington’s Disease

Author

Mrzljak, Ladislav, Munoz-Sanjuan, Ignacio, Geyer, Mark A., Series editor, Ellenbroek, Bart A., Series editor, Marsden, Charles A., Series editor, Barnes, Thomas R.E., Series editor, Nguyen, Hoa Huu Phuc, editor, and Cenci, M. Angela, editor

Published
2015
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24. Design and evaluation of [¹⁸F]CHDI-650 as a positron emission tomography ligand to image mutant Huntingtin aggregates

Author

Liu, Longbin, Johnson, Peter D., Prime, Michael E., Khetarpal, Vinod, Brown, Christopher J., Anzillotti, Luca, Bertoglio, Daniele, Chen, Xuemei, Coe, Samuel, Davis, Randall, Dickie, Anthony P., Esposito, Simone, Gadouleau, Elise, Giles, Paul R., Greenaway, Catherine, Haber, James, Halldin, Christer, Haller, Scott, Hayes, Sarah, Herbst, Todd, Herrmann, Frank, Hessmann, Manuela, Hsai, Ming Min, Khani, Yaser, Kotey, Adrian, Lembo, Angelo, Mangette, John E., Marriner, Gwendolyn A., Marston, Richard W., Mills, Matthew R., Monteagudo, Edith, Forsberg-Moren, Anton, Nag, Sangram, Orsatti, Laura, Sandiego, Christine, Schaertl, Sabine, Sproston, Joanne, Staelens, Steven, Tookey, Jack, Turner, Penelope A., Vecchi, Andrea, Veneziano, Maria, Munoz-Sanjuan, Ignacio, Bard, Jonathan, and Dominguez, Celia

Subjects
Pharmacology. Therapy
Abstract

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

Published
2023

30. Longitudinal investigation of changes in resting-state co-activation patterns and their predictive ability in the zQ175 DN mouse model of Huntington’s disease

Author

Adhikari, Mohit H., primary, Vasilkovska, Tamara, additional, Cachope, Roger, additional, Tang, Haiying, additional, Liu, Longbin, additional, Keliris, Georgios A., additional, Munoz-Sanjuan, Ignacio, additional, Pustina, Dorian, additional, Van der Linden, Annemie, additional, and Verhoye, Marleen, additional

Published
2022
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31. I09 A Huntington’s disease embryonic stem cell phenotypic hts to identify small molecule modulators of mutant huntingtin

Author

Todd, Daniel, primary, Stebbeds, Marta, additional, Thatcher, Emma, additional, Barnard, Amy, additional, Anton, Jeremy, additional, Sienerth, Arnold, additional, Visser, Mijke, additional, Mitchell, Philip, additional, Breccia, Perla, additional, Smith, David, additional, McAllister, George, additional, Haque, Tasir, additional, Liu, Longbin, additional, Dominguez, Celia, additional, and Munoz-Sanjuan, Ignacio, additional

Published
2022
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34. Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington’s Disease

Author

Ladduwahetty, Tammy, primary, Lee, Matthew R., additional, Maillard, Michel C., additional, Cachope, Roger, additional, Todd, Daniel, additional, Barnes, Michael, additional, Beaumont, Vahri, additional, Chauhan, Alka, additional, Gallati, Caroline, additional, Haughan, Alan F., additional, Kempf, Georg, additional, Luckhurst, Christopher A., additional, Matthews, Kim, additional, McAllister, George, additional, Mitchell, Philip, additional, Patel, Hiral, additional, Rose, Mark, additional, Saville-Stones, Elizabeth, additional, Steinbacher, Stefan, additional, Stott, Andrew J., additional, Thatcher, Emma, additional, Tierney, Jason, additional, Urbonas, Liudvikas, additional, Munoz-Sanjuan, Ignacio, additional, and Dominguez, Celia, additional

Published
2022
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35. Exploiting differences in caspase-2 and -3 S 2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors

Author

Maillard, Michel C., Brookfield, Frederick A., Courtney, Stephen M., Eustache, Florence M., Gemkow, Mark J., Handel, Rebecca K., Johnson, Laura C., Johnson, Peter D., Kerry, Mark A., Krieger, Florian, Meniconi, Mirco, Muñoz-Sanjuán, Ignacio, Palfrey, Jordan J., Park, Hyunsun, Schaertl, Sabine, Taylor, Malcolm G., Weddell, Derek, and Dominguez, Celia

Published
2011
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37. Development of mAb-based polyglutamine-dependent and polyglutamine length-independent huntingtin quantification assays with cross-site validation

Author

Fischer, David F., primary, Dijkstra, Sipke, additional, Lo, Kimberly, additional, Suijker, Johnny, additional, Correia, Ana C. P., additional, Naud, Patricia, additional, Poirier, Martin, additional, Tessari, Michela A., additional, Boogaard, Ivette, additional, Flynn, Geraldine, additional, Visser, Mijke, additional, Lamers, Marieke B. A. C., additional, McAllister, George, additional, Munoz-Sanjuan, Ignacio, additional, and Macdonald, Douglas, additional

Published
2022
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38. Validation, kinetic modeling, and test-retest reproducibility of [¹⁸F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice

Author

Bertoglio, Daniele, Zajicek, Franziska, De Lombaerde, Stef, Miranda Menchaca, Alan, Stroobants, Sigrid, Wang, Yuchuan, Dominguez, Celia, Munoz-Sanjuan, Ignacio, Bard, Jonathan, Liu, Longbin, Verhaeghe, Jeroen, and Staelens, Steven

Subjects
Human medicine
Abstract

Alterations in synaptic vesicle glycoprotein 2 A (SV2A) have been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, SV2A positron emission tomography (PET) imaging may provide a unique tool to investigate synaptic density dynamics during disease progression and after therapeutic intervention. This study aims to extensively characterize the novel radioligand [18F]SynVesT-1 for preclinical applications. In C57Bl/6J mice (n = 39), we assessed the plasma profile of [18F]SynVesT-1, validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function (AIF), performed a blocking study with levetiracetam (50 and 200 mg/kg, i.p.) to verify the specificity towards SV2A, examined kinetic models for volume of distribution (VT) quantification, and explored test-retest reproducibility of [18F]SynVesT-1 in the central nervous system (CNS). Plasma availability of [18F]SynVesT-1 decreased rapidly (13.4 ± 1.5% at 30 min post-injection). VT based on AIF and IDIF showed excellent agreement (r2 = 0.95, p

Published
2022

39. Longitudinal preclinical evaluation of the novel radioligand [¹¹C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington's disease

Author

Bertoglio, Daniele, Verhaeghe, Jeroen, Miranda Menchaca, Alan, Wyffels, Leonie, Stroobants, Sigrid, Mrzljak, Ladislav, Khetarpal, Vinod, Skinbjerg, Mette, Liu, Longbin, Dominguez, Celia, Munoz-Sanjuan, Ignacio, Bard, Jonathan, and Staelens, Steven

Subjects
Human medicine
Abstract

Purpose As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington's disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [C-11]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD. Methods After evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [H-3]CHDI-626 autoradiography. Results Despite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3 M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [H-3]CHDI-626 autoradiography. Conclusion With clinical evaluation underway, [C-11]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.

Published
2022

40. sj-pdf-1-jcb-10.1177_0271678X221101648 - Supplemental material for Validation, kinetic modeling, and test-retest reproducibility of [18F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice

Author

Bertoglio, Daniele, Zajicek, Franziska, Lombaerde, Stef De, Miranda, Alan, Stroobants, Sigrid, Wang, Yuchuan, Dominguez, Celia, Munoz-Sanjuan, Ignacio, Bard, Jonathan, Liu, Longbin, Verhaeghe, Jeroen, and Staelens, Steven

Subjects
110320 Radiology and Organ Imaging, FOS: Clinical medicine, FOS: Biological sciences, Medicine, Cell Biology, 110305 Emergency Medicine, 110306 Endocrinology, Biochemistry, 69999 Biological Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X221101648 for Validation, kinetic modeling, and test-retest reproducibility of [18F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice by Daniele Bertoglio, Franziska Zajicek, Stef De Lombaerde, Alan Miranda, Sigrid Stroobants, Yuchuan Wang, Celia Dominguez, Ignacio Munoz-Sanjuan, Jonathan Bard, Longbin Liu, Jeroen Verhaeghe and Steven Staelens in Journal of Cerebral Blood Flow & Metabolism

Published
2022
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41. Longitudinal investigation of changes in resting-state co-activation patterns and their predictive ability in the zQ175 DN mouse model of Huntington’s disease

Author

Adhikari, Mohit, Vasilkovska, Tamara, Cachope, Roger, Tang, Haiying, Liu, Longbin, Keliris, Georgios, Munoz-Sanjuan, Ignacio, Pustina, Dorian, Van Der Linden, Anne-Marie, and Verhoye, Marleen

Subjects
Pharmacology. Therapy
Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by expanded (≥40) glutamine-encoding CAG repeats in the huntingtin gene, which leads to dysfunction and death of predominantly striatal and cortical neurons. While the genetic profile and behavioural signs of the disease are better known, changes in the functional architecture of the brain, especially before the behavioural symptoms become apparent, are not fully and consistently characterized. In this study, we sought markers at pre, early and late manifest states of phenotypic progression in the heterozygous (HET) zQ175 delta-neo (DN) mouse model, using resting-state functional magnetic resonance imaging (RS-fMRI). This mouse model shows molecular, cellular and circuitry alterations that resemble those seen in HD in humans. Specifically, we investigated, longitudinally, changes in co-activation patterns (CAPs) that are the transient states of brain activity constituting the resting-state networks (RSNs). Most robust changes in the temporal properties of CAPs occurred at the late manifest state; the durations of two anti-correlated CAPs, characterized by simultaneous co-activation of default-mode like network (DMLN) and co-deactivation of lateral-cortical network (LCN) and vice-versa, were reduced in the zQ175 DN HET animals compared to the wild-type mice. Changes in the spatial properties, measured in terms of activation levels of different brain regions, during CAPs were found at all three states and became progressively more pronounced at the manifest states. We then assessed the cross-validated predictive power of CAP metrics to distinguish HET animals from controls. Spatial properties of CAPs performed significantly better than the chance level at all three states with 80% classification accuracy at the early and late manifest states.

Published
2022

42. Synaptic vesicle glycoprotein 2A is affected in the CNS of Huntington’s Disease mice and post-mortem human HD brain

Author

Bertoglio, Daniele, Verhaeghe, Jeroen, Wyffels, Leonie, Miranda Menchaca, Alan, Stroobants, Sigrid, Mrzljak, Ladislav, Dominguez, Celia, Skinbjerg, Mette, Bard, Jonathan, Liu, Longbin, Munoz-Sanjuan, Ignacio, and Staelens, Steven

Subjects
fluids and secretions, embryonic structures, Human medicine
Abstract

Synaptic dysfunction is a primary mechanism underlying Huntington’s Disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of 11C-UCB-J microPET imaging in the central nervous system (CNS) of HD mice. METHODS: Dynamic 11C-UCB-J microPET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 months, M) in the heterozygous knock-in Q175DN mouse model of HD and WT littermates (n = 16-18/genotype and time point). Cerebral 11C-UCB-J analyses were performed to assess genotypic differences during pre-symptomatic (3M) and symptomatic (7-16M) disease stages. 11C-UCB-J binding in the spinal cord was quantified at 16M. 3H-UCB-J autoradiography and SV2A immunofluorescence were performed post-mortem in mouse and human brain tissue. RESULTS: 11C-UCB-J binding was declined in symptomatic heterozygous mice compared to WT littermates in parallel with disease progression (7M: p

Published
2022

44. Development of a ligand for in vivo imaging of mutant huntingtin in Huntington’s disease

Author

Bertoglio, Daniele, primary, Bard, Jonathan, additional, Hessmann, Manuela, additional, Liu, Longbin, additional, Gärtner, Annette, additional, De Lombaerde, Stef, additional, Huscher, Britta, additional, Zajicek, Franziska, additional, Miranda, Alan, additional, Peters, Finn, additional, Herrmann, Frank, additional, Schaertl, Sabine, additional, Vasilkovska, Tamara, additional, Brown, Christopher J., additional, Johnson, Peter D., additional, Prime, Michael E., additional, Mills, Matthew R., additional, Van der Linden, Annemie, additional, Mrzljak, Ladislav, additional, Khetarpal, Vinod, additional, Wang, Yuchuan, additional, Marchionini, Deanna M., additional, Skinbjerg, Mette, additional, Verhaeghe, Jeroen, additional, Dominguez, Celia, additional, Staelens, Steven, additional, and Munoz-Sanjuan, Ignacio, additional

Published
2022
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47. Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [11C]CHDI-00485180-R and [11C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin.

Author

Delva, Aline, Koole, Michel, Serdons, Kim, Bormans, Guy, Liu, Longbin, Bard, Jonathan, Khetarpal, Vinod, Dominguez, Celia, Munoz-Sanjuan, Ignacio, Wood, Andrew, Skinbjerg, Mette, Wang, Yuchuan, Vandenberghe, Wim, and Van Laere, Koen

Subjects
POSITRON emission tomography, RADIATION dosimetry, HUNTINGTIN protein, NEUROTOXICOLOGY, ADVERSE health care events
Abstract

Purpose: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. Methods: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. Results: There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9 μGy/MBq), heart wall (15.9 μGy/MBq) and small intestine (15.8 μGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5 μGy/MBq), small intestine (20.4 μGy/MBq) and liver (19.6 μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. Conclusion: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. Trial registration : EudraCT number 2020-002129-27. Clinicaltrials.gov NCT05224115 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Published
2022
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48. Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington’s disease

Author

Bertoglio, Daniele, primary, Verhaeghe, Jeroen, additional, Miranda, Alan, additional, Wyffels, Leonie, additional, Stroobants, Sigrid, additional, Mrzljak, Ladislav, additional, Khetarpal, Vinod, additional, Skinbjerg, Mette, additional, Liu, Longbin, additional, Dominguez, Celia, additional, Munoz-Sanjuan, Ignacio, additional, Bard, Jonathan, additional, and Staelens, Steven, additional

Published
2021
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49. HDinHD: A Rich Data Portal for Huntington’s Disease Research

Author

Aaronson, Jeff, primary, Beaumont, Vahri, additional, Blevins, Richard A., additional, Andreeva, Viktoria, additional, Murasheva, Irina, additional, Shneyderman, Anastasia, additional, Armah, Kabenla, additional, Gill, Rob, additional, Chen, Jian, additional, Rosinski, Jim, additional, Park, Larry C., additional, Coppola, Giovanni, additional, Munoz-Sanjuan, Ignacio, additional, and Vogt, Thomas F., additional

Published
2021
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50. Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem

Author

Bertoglio, Daniele, primary, Verhaeghe, Jeroen, additional, Wyffels, Leonie, additional, Miranda, Alan, additional, Stroobants, Sigrid, additional, Mrzljak, Ladislav, additional, Dominguez, Celia, additional, Skinbjerg, Mette, additional, Bard, Jonathan, additional, Liu, Longbin, additional, Munoz-Sanjuan, Ignacio, additional, and Staelens, Steven, additional

Published
2021
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