Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase

  • ACS Med Chem Lett. 2013 Apr 20;4(6):509-13. doi: 10.1021/ml4000996.
Ping Liu  1 Terence G Hamill  2 Marc Chioda  1 Harry Chobanian  1 Selena Fung  1 Yan Guo  1 Linda Chang  1 Raman Bakshi  1 Qingmei Hong  1 James Dellureficio  1 Linus S Lin  1 Catherine Abbadie  1 Jessica Alexander  1 Hong Jin  1 Suzanne Mandala  1 Lin-Lin Shiao  1 Wenping Li  2 Sandra Sanabria  2 David Williams  2 Zhizhen Zeng  2 Richard Hajdu  1 Nina Jochnowitz  1 Mark Rosenbach  1 Bindhu Karanam  1 Maria Madeira  1 Gino Salituro  1 Joyce Powell  1 Ling Xu  1 Jenna L Terebetski  1 Joseph F Leone  1 Patricia Miller  2 Jacquelynn Cook  2 Marie Holahan  2 Aniket Joshi  2 Stacey O'Malley  2 Mona Purcell  2 Diane Posavec  2 Tsing-Bau Chen  2 Kerry Riffel  2 Mangay Williams  2 Richard Hargreaves  2 Kathleen A Sullivan  1 Ravi P Nargund  1 Robert J DeVita  1
Affiliations
  • 1. Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • 2. Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
Abstract

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.

Keywords
FAAH; Fatty acid amide hydrolase; PET tracer; biomarker; carbon-11; positron emission tomography; target engagement.
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