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Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.
Liu, Longbin; Johnson, Peter D; Prime, Michael E; Khetarpal, Vinod; Brown, Christopher J; Anzillotti, Luca; Bertoglio, Daniele; Chen, Xuemei; Coe, Samuel; Davis, Randall; Dickie, Anthony P; Esposito, Simone; Gadouleau, Elise; Giles, Paul R; Greenaway, Catherine; Haber, James; Halldin, Christer; Haller, Scott; Hayes, Sarah; Herbst, Todd; Herrmann, Frank; Heßmann, Manuela; Hsai, Ming Min; Khani, Yaser; Kotey, Adrian; Lembo, Angelo; Mangette, John E; Marriner, Gwendolyn A; Marston, Richard W; Mills, Matthew R; Monteagudo, Edith; Forsberg-Morén, Anton; Nag, Sangram; Orsatti, Laura; Sandiego, Christine; Schaertl, Sabine; Sproston, Joanne; Staelens, Steven; Tookey, Jack; Turner, Penelope A; Vecchi, Andrea; Veneziano, Maria; Muñoz-Sanjuan, Ignacio; Bard, Jonathan; Dominguez, Celia.
Afiliação
  • Liu L; CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
  • Johnson PD; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Prime ME; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Khetarpal V; CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
  • Brown CJ; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Anzillotti L; Experimental Pharmacology Department, IRBM S.p.A., Via Pontina km 30,600, Pomezia, Roma 00071, Italy.
  • Bertoglio D; Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
  • Chen X; Curia Global, Inc., 1001 Main Street, Buffalo, New York 14203, United States.
  • Coe S; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Davis R; Curia Global, Inc., 1001 Main Street, Buffalo, New York 14203, United States.
  • Dickie AP; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Esposito S; Experimental Pharmacology Department, IRBM S.p.A., Via Pontina km 30,600, Pomezia, Roma 00071, Italy.
  • Gadouleau E; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Giles PR; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Greenaway C; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Haber J; Curia Global, Inc., 1001 Main Street, Buffalo, New York 14203, United States.
  • Halldin C; Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Hospital, Karolinska Institutet, Stockholm S-17176, Sweden.
  • Haller S; Charles River Laboratories, 54943 North Main Street, Mattawan, Michigan 49071, United States.
  • Hayes S; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Herbst T; CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
  • Herrmann F; Evotec SE, Manfred Eigen Campus, Essener Bogen 7, Hamburg 22419, Germany.
  • Heßmann M; Evotec SE, Manfred Eigen Campus, Essener Bogen 7, Hamburg 22419, Germany.
  • Hsai MM; Curia Global, Inc., 1001 Main Street, Buffalo, New York 14203, United States.
  • Khani Y; Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Hospital, Karolinska Institutet, Stockholm S-17176, Sweden.
  • Kotey A; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Lembo A; Experimental Pharmacology Department, IRBM S.p.A., Via Pontina km 30,600, Pomezia, Roma 00071, Italy.
  • Mangette JE; Curia Global, Inc., 1001 Main Street, Buffalo, New York 14203, United States.
  • Marriner GA; Charles River Laboratories, 54943 North Main Street, Mattawan, Michigan 49071, United States.
  • Marston RW; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Mills MR; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Monteagudo E; CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
  • Forsberg-Morén A; Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Hospital, Karolinska Institutet, Stockholm S-17176, Sweden.
  • Nag S; Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Hospital, Karolinska Institutet, Stockholm S-17176, Sweden.
  • Orsatti L; Experimental Pharmacology Department, IRBM S.p.A., Via Pontina km 30,600, Pomezia, Roma 00071, Italy.
  • Sandiego C; Invicro, 60 Temple St, Ste 8A, New Haven, Connecticut 06510, United States.
  • Schaertl S; Evotec SE, Manfred Eigen Campus, Essener Bogen 7, Hamburg 22419, Germany.
  • Sproston J; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Staelens S; Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
  • Tookey J; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Turner PA; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, U.K.
  • Vecchi A; Experimental Pharmacology Department, IRBM S.p.A., Via Pontina km 30,600, Pomezia, Roma 00071, Italy.
  • Veneziano M; Experimental Pharmacology Department, IRBM S.p.A., Via Pontina km 30,600, Pomezia, Roma 00071, Italy.
  • Muñoz-Sanjuan I; CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
  • Bard J; CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
  • Dominguez C; CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
J Med Chem ; 66(1): 641-656, 2023 01 12.
Article em En | MEDLINE | ID: mdl-36548390
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Huntington / Tomografia por Emissão de Pósitrons Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Huntington / Tomografia por Emissão de Pósitrons Idioma: En Ano de publicação: 2023 Tipo de documento: Article