Design and Evaluation of [<sup>18</sup>F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates
Longbin Liu, Peter Johnson, Michael E. Prime, Vinod Khetarpal, Christopher J. Brown, Luca Anzillotti, Daniele Bertoglio, Xuemei Chen, Samuel Coe, Randall Davis, Anthony P. Dickie, Simone Esposito, Elise Gadouleau, Paul R. Giles, Catherine Greenaway, James C. Haber, Christer Halldin, Scott Haller, Sarah A. Hayes, Todd Herbst, Frank Herrmann, Manuela Heßmann, Ming Min Hsai, Yaser Khani, Adrian Kotey, Angelo Lembo, John E. Mangette, Gwendolyn A. Marriner, Richard W. Marston, Matthew R. Mills, Edith Monteagudo, Anton Forsberg-Morén, Sangram Nag, Laura Orsatti, Christine Sandiego, Sabine Schaertl, Joanne L. Sproston, Steven Staelens, Jack Tookey, Penelope A. Turner, Andrea Vecchi, Maria Veneziano, Ignacio Muñoz-Sanjuán, Jonathan Bard, Celia Dominguez
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.