2. Academic Validation
  3. [11C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins

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

  • J Med Chem. 2021 Aug 26;64(16):12003-12021. doi: 10.1021/acs.jmedchem.1c00667.
Longbin Liu 1,  Peter D Johnson 2,  Michael E Prime 2,  Vinod Khetarpal 1,  Matthew R Lee 1,  Christopher J Brown 2,  Xuemei Chen 3,  Daniel Clark-Frew 2,  Samuel Coe 2,  Mike Conlon 3,  Randall Davis 3,  Samantha Ensor 3,  Simone Esposito 4,  Anton Forsberg Moren 5,  Xinjie Gai 2,  Samantha Green 2,  Catherine Greenaway 2,  James Haber 3,  Christer Halldin 5,  Sarah Hayes 2,  Todd Herbst 1,  Frank Herrmann 6,  Manuela Heßmann 6,  Ming Min Hsai 3,  Adrian Kotey 2,  John E Mangette 3,  Matthew R Mills 2,  Edith Monteagudo 1,  Sangram Nag 5,  Martina Nibbio 4,  Laura Orsatti 4,  Sabine Schaertl 6,  Christoph Scheich 6,  Joanne Sproston 2,  Vladimir Stepanov 5,  Katarina Varnäs 5,  Andrea Varrone 5,  John Wityak 1,  Ladislav Mrzljak 1,  Ignacio Munoz-Sanjuan 1,  Jonathan A Bard 1,  Celia Dominguez 1
Affiliations

Affiliations

  • 1 CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
  • 2 Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • 3 Albany Molecular Research, Inc., 1001 Main Street, Buffalo, New York 14203, United States.
  • 4 IRBM, IRBM Science Park S.p.A., Via Pontina Km 30,600, Pomezia, Rome 00071, Italy.
  • 5 Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Hospital, Karolinska Institutet, Stockholm S-17176, Sweden.
  • 6 Evotec SE, Manfred Eigen Campus, Essener Bogen 7, Hamburg 22419, Germany.
PMID: 34351166 DOI: 10.1021/acs.jmedchem.1c00667
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.

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