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.
Subject(s)
Huntington Disease , Positron-Emission Tomography , Animals , Humans , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Ligands , Positron-Emission Tomography/methods , Huntington Disease/diagnostic imaging , Huntington Disease/drug therapy , Brain/diagnostic imaging , Brain/metabolismABSTRACT
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 Aß- 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.
Subject(s)
Brain/diagnostic imaging , Heterocyclic Compounds, 3-Ring/chemistry , Huntingtin Protein/metabolism , Protein Aggregates/physiology , Pyridines/chemistry , Radiopharmaceuticals/chemistry , Alzheimer Disease , Animals , Biomarkers/metabolism , Brain/metabolism , Carbon Radioisotopes/chemistry , Female , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Macaca fascicularis , Male , Mice, Inbred C57BL , Molecular Structure , Positron-Emission Tomography , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Huntingtin Protein/analysis , Huntington Disease/diagnostic imaging , Positron-Emission Tomography/methods , Protein Aggregation, Pathological/diagnostic imaging , Animals , Disease Models, Animal , Dogs , Female , Humans , Huntingtin Protein/genetics , Huntington Disease/genetics , Ligands , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred C57BL , Mutation , Peptides/genetics , Protein Aggregation, Pathological/genetics , Radiopharmaceuticals/analysis , Rats, Sprague-DawleyABSTRACT
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.
