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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