Development of a ligand for in vivo imaging of mutant huntingtin in Huntington’s disease
Daniele Bertoglio, Jonathan Bard, Manuela Heßmann, Longbin Liu, Annette Gärtner, Stef De Lombaerde, Britta Huscher, Franziska Zajicek, Alan Miranda, Finn Peters, Frank Herrmann, Sabine Schaertl, Tamara Vasilkovska, Christopher J. Brown, Peter Johnson, Michael E. Prime, Matthew R. Mills, Annemie Van der Linden, Ladislav Mrzljak, Vinod Khetarpal, Yuchuan Wang, Deanna M. Marchionini, Mette Skinbjerg, Jeroen Verhaeghe, Celia Dominguez, Steven Staelens, Ignacio Muñoz-Sanjuán
Abstract
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin ( HTT ) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11 C ([ 11 C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.