[11C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins

Autor: 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, Sarah Hayes
Rok vydání: 2021
Předmět:
Zdroj: Journal of Medicinal Chemistry. 64:12003-12021
ISSN: 1520-4804
0022-2623
DOI: 10.1021/acs.jmedchem.1c00667
Popis: 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.
Databáze: OpenAIRE
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