[<sup>11</sup>C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins
Longbin Liu, Peter Johnson, Michael E. Prime, Vinod Khetarpal, Matthew R. Lee, Christopher J. Brown, Xuemei Chen, Daniel Clark-Frew, Samuel Coe, Mike Conlon, Randall Davis, Samantha F. Ensor, Simone Esposito, Anton Forsberg Morén, Xinjie Gai, Samantha Green, Catherine Greenaway, James C. Haber, Christer Halldin, Sarah A. Hayes, Todd Herbst, Frank Herrmann, Manuela Heßmann, Ming Min Hsai, Adrian Kotey, John E. Mangette, Matthew R. Mills, Edith Monteagudo, Sangram Nag, Martina Nibbio, Laura Orsatti, Sabine Schaertl, Christoph Scheich, Joanne L. Sproston, В. А. Степанов, Katarina Varnäs, Andrea Varrone, John Wityak, Ladislav Mrzljak, Ignacio Muñoz-Sanjuán, Jonathan Bard, Celia Dominguez
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.