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Research ArticleDrug Discovery and Translational Medicine

In vitro pharmacological characterization and in vivo validation of LSN3172176 a novel M1 selective muscarinic receptor agonist tracer molecule for positron emission tomography (PET)

Adrian J Mogg, Thomas Eessalu, Megan Johnson, Rebecca Wright, Helen E Sanger, Hongling Xiou, Michael Crabtree, Alex Smith, Ellen Colvin, Douglas Schober, Donald Gehlert, Cynthia Jesudason, Paul Goldsmith, Michael P Johnson, Christian C Felder, Vanessa N Barth and Lisa M Broad
Journal of Pharmacology and Experimental Therapeutics April 11, 2018, jpet.117.246454; DOI: https://doi.org/10.1124/jpet.117.246454
Adrian J Mogg
Lilly Research Laboratories, Eli Lilly & Co., Erl Wood Manor, United Kingdom;
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Thomas Eessalu
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Megan Johnson
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Rebecca Wright
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Helen E Sanger
Lilly Research Laboratories, Eli Lilly & Co., Erl Wood Manor, United Kingdom;
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Hongling Xiou
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Michael Crabtree
Lilly Research Laboratories, Eli Lilly & Co., Erl Wood Manor, United Kingdom;
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Alex Smith
Lilly Research Laboratories, Eli Lilly & Co., Erl Wood Manor, United Kingdom;
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Ellen Colvin
Lilly Research Laboratories, Eli Lilly & Co., Erl Wood Manor, United Kingdom;
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Douglas Schober
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Donald Gehlert
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Cynthia Jesudason
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Paul Goldsmith
Lilly Research Laboratories, Eli Lilly & Co., Erl Wood Manor, United Kingdom;
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Michael P Johnson
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Christian C Felder
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Vanessa N Barth
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis
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Lisa M Broad
Lilly Research Laboratories, Eli Lilly & Co., Erl Wood Manor, United Kingdom;
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Abstract

In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable and validated biomarkers. One valuable approach to assessing target engagement is to utilize PET tracers. In this study we describe the pharmacological characterization of a selective M1 agonist amenable for in vivo tracer studies. We utilized a novel direct binding assay to identify non-radiolabelled ligands, including LSN3172176, with the favourable characteristics required for a PET tracer. In vitro functional and radioligand binding experiments revealed that LSN3172176 was a potent partial agonist (EC50 2.4-7.0nM, Emax 43%-73%, displaying binding selectivity for M1 mAChRs (Kd = 1.5nM) which was conserved across species (native tissue Kd=1.02, 2.66, 8, & 1.03 at mouse, rat, monkey and human respectively). Overall selectivity of LSN3172176 appeared to be a product of potency and stabilization of the high-affinity state of the M1 receptor, relative to other mAChR subtypes (M1>M2,M4,M5>M3). In vivo, use of wild-type and mAChR knock-out mice further supported the M1-preferring selectivity profile of LSN3172176 for the M1 receptor (78% reduction in cortical occupancy in M1 KO mice). These findings support the development of LSN3172176 as a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.

  • Alzheimer's Disease
  • drug development
  • drug discovery
  • muscarinic cholinergic receptors
  • muscarinic receptors
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 365 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 365, Issue 2
1 May 2018
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Research ArticleDrug Discovery and Translational Medicine

In vitro pharmacological characterization and in vivo validation of LSN3172176 a novel M1 selective muscarinic receptor agonist tracer molecule for positron emission tomography (PET)

Adrian J Mogg, Thomas Eessalu, Megan Johnson, Rebecca Wright, Helen E Sanger, Hongling Xiou, Michael Crabtree, Alex Smith, Ellen Colvin, Douglas Schober, Donald Gehlert, Cynthia Jesudason, Paul Goldsmith, Michael P Johnson, Christian C Felder, Vanessa N Barth and Lisa M Broad
Journal of Pharmacology and Experimental Therapeutics April 11, 2018, jpet.117.246454; DOI: https://doi.org/10.1124/jpet.117.246454

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Research ArticleDrug Discovery and Translational Medicine

In vitro pharmacological characterization and in vivo validation of LSN3172176 a novel M1 selective muscarinic receptor agonist tracer molecule for positron emission tomography (PET)

Adrian J Mogg, Thomas Eessalu, Megan Johnson, Rebecca Wright, Helen E Sanger, Hongling Xiou, Michael Crabtree, Alex Smith, Ellen Colvin, Douglas Schober, Donald Gehlert, Cynthia Jesudason, Paul Goldsmith, Michael P Johnson, Christian C Felder, Vanessa N Barth and Lisa M Broad
Journal of Pharmacology and Experimental Therapeutics April 11, 2018, jpet.117.246454; DOI: https://doi.org/10.1124/jpet.117.246454
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