2. Academic Validation
  3. Discovery of [11C]MK-6884: A Positron Emission Tomography (PET) Imaging Agent for the Study of M4Muscarinic Receptor Positive Allosteric Modulators (PAMs) in Neurodegenerative Diseases

Discovery of [11C]MK-6884: A Positron Emission Tomography (PET) Imaging Agent for the Study of M4Muscarinic Receptor Positive Allosteric Modulators (PAMs) in Neurodegenerative Diseases

  • J Med Chem. 2020 Mar 12;63(5):2411-2425. doi: 10.1021/acs.jmedchem.9b01406.
Ling Tong 1,  Wenping Li 2,  Michael Man-Chu Lo 3,  Xiaolei Gao 3,  Jenny Miu-Chen Wai 1,  Michael Rudd 1,  David Tellers 1,  Aniket Joshi 2,  Zhizhen Zeng 2,  Patricia Miller 2,  Cristian Salinas 2,  Kerry Riffel 2,  Hyking Haley 2,  Mona Purcell 2,  Marie Holahan 2,  Liza Gantert 2,  Jeffrey W Schubert 1,  Kristen Jones 1,  James Mulhearn 1,  Melissa Egbertson 1,  Zhaoyang Meng 1,  Barbara Hanney 1,  Robert Gomez 1,  Scott T Harrison 1,  Paul McQuade 2,  Tjerk Bueters 4,  Jason Uslaner 5,  John Morrow 5,  Fiona Thomson 5,  Jongrock Kong 6,  Jing Liao 6,  Oleg Selyutin 3,  Jianming Bao 3,  Nicholas B Hastings 5,  Sony Agrawal 5,  Brian C Magliaro 5,  Frederick J Monsma Jr 5,  Michelle D Smith 5,  Stefania Risso 5,  David Hesk 6,  Eric Hostetler 2,  Robert Mazzola 3
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
  • 2 Translational Biomarkers, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
  • 3 Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 4 Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
  • 5 Discovery Biology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
  • 6 Department of Process Research and Development, Merck & Co., Inc., 126 East Lincoln Avenue Rahway, New Jersey 07065, United States.
PMID: 32101422 DOI: 10.1021/acs.jmedchem.9b01406
Abstract

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and Others have investigated Muscarinic Acetylcholine Receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.

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