4 results on '"Catherine Greenaway"'
Search Results
2. [11C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins
- Author
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Vinod Khetarpal, Catherine Greenaway, Samantha Ensor, Randall Davis, Michael Conlon, Andrea Varrone, Frank Herrmann, Laura Orsatti, Xuemei Chen, Martina Nibbio, Christer Halldin, Vladimir Stepanov, Simone Esposito, Daniel Clark-Frew, Ladislav Mrzljak, Christoph Scheich, Sabine Schaertl, Todd Herbst, Ming Min Hsai, Peter Johnson, Samuel Coe, Jonathan Bard, John Wityak, Michael Prime, Katarina Varnäs, Adrian Kotey, Lee Matthew, Sangram Nag, Manuela Heßmann, Celia Dominguez, Samantha Green, James C. Haber, Xinjie Gai, Longbin Liu, Edith Monteagudo, Anton Forsberg Morén, John E. Mangette, Christopher J. Brown, Matthew R. Mills, Ignacio Munoz-Sanjuan, Joanne Sproston, and Sarah Hayes
- Subjects
Huntingtin ,medicine.diagnostic_test ,Chemistry ,Mutant ,Medium spiny neuron ,Positron emission tomography ,Free fraction ,Drug Discovery ,medicine ,Cancer research ,Molecular Medicine ,Neuronal degeneration ,Pet tracer ,Pathological - Abstract
The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-a]pyrimidine series that show selective binding to mHTT aggregates over Aβ- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [11C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.
- Published
- 2021
3. Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand
- Author
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Michael Prime, Samantha Green, Celia Dominguez, Edith Monteagudo, Malcolm Taylor, Akihiro Takano, Longbin Liu, Adrian Kotey, Wayne Thomas, Zhisheng Jia, Anthony P Dickie, Catherine Greenaway, Samuel Coe, Miklós Tóth, John Wityak, Vinod Khetarpal, Sergio Menta, Simone Esposito, Katarina Vanräs, Andreas Ebneth, John E. Mangette, Ian Wigginton, Todd Herbst, Peter Johnson, Sabine Schaertl, Vladimir Stepanov, Jonathan Bard, Sebastien Galan, Elise Gadouleau, Randall Davis, Christopher John Brown, Frank Herrmann, Richard W Marston, Darshan Gunvant Vaidya, Laura Orsatti, Xuemei Chen, Martina Nibbio, Manuela Heßmann, Joanne Sproston, Matthew R Mills, Ignacio Munoz-Sanjuan, Daniel Clark-Frew, Derek Alexander Weddell, Ladislav Mrzljak, Christoph Scheich, Xinjie Gai, Christer Halldin, Sangram Nag, Lee Matthew, Patricia Miranda-Azpiazu, Paul Giles, Thomas Krulle, Alexander Kiselyov, Marie Svedberg, and Sarah Hayes
- Subjects
Male ,Huntingtin ,Imaging biomarker ,Mutant ,Protein aggregation ,medicine.disease_cause ,Ligands ,01 natural sciences ,Protein Aggregation, Pathological ,Madin Darby Canine Kidney Cells ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,Dogs ,Drug Discovery ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Mutation ,Huntingtin Protein ,medicine.diagnostic_test ,Chemistry ,Ligand (biochemistry) ,0104 chemical sciences ,Cell biology ,Mice, Inbred C57BL ,010404 medicinal & biomolecular chemistry ,Disease Models, Animal ,Huntington Disease ,Positron emission tomography ,Positron-Emission Tomography ,Molecular Medicine ,Female ,Efflux ,Radiopharmaceuticals ,Peptides - Abstract
Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
- Published
- 2020
4. Critical timing of gastrostomy insertion in a child with cystic fibrosis
- Author
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Catherine Greenaway, Simon R Clarke, Ian M. Balfour-Lynn, and Christopher J. Grime
- Subjects
Pulmonary and Respiratory Medicine ,Pediatrics ,medicine.medical_specialty ,Malabsorption ,Time Factors ,Cystic Fibrosis ,medicine.medical_treatment ,Nutritional Status ,Poor weight gain ,Cystic fibrosis ,Enteral Nutrition ,Fatal Outcome ,Intervention (counseling) ,medicine ,Humans ,Child ,Lung function ,Gastrostomy ,business.industry ,Body Weight ,medicine.disease ,Body Height ,Pediatrics, Perinatology and Child Health ,Female ,business ,Tomography, X-Ray Computed ,Body mass index - Abstract
Pulmonary exacerbations and malabsorption in children with cystic fibrosis (CF) can lead to faltering growth and poor weight gain. Children with a higher BMI (body mass index) show a slower decline in lung function. Our specialist CF centre has experienced a death following gastrostomy insertion in a young CF child, despite maximal medical intervention, which has made us reflect on our practice and the urgency with which we discuss the option for a gastrostomy to improve nutrition.
- Published
- 2015
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