Discovery of [11C]MK-8056: A Selective PET Imaging Agent for the Study of mGluR2 Negative Allosteric Modulators

James J Perkins; Paul McQuade; Christopher J Bungard; Tracy L Diamond; Liza T Gantert; Anthony L Gotter; Barbara Hanney; Ivory D Hills; Danielle M Hurzy; Aniket Joshi; Jonathan T Kern; Kelly-Ann S Schlegel; Jesse J Manikowski; Zhaoyang Meng; Julie A O'Brien; Anthony J Roecker; Sean M Smith; Jason M Uslaner; Eric Hostetler; Robert S Meissner

doi:10.1021/acsmedchemlett.3c00175

Discovery of [¹¹C]MK-8056: A Selective PET Imaging Agent for the Study of mGluR₂ Negative Allosteric Modulators

ACS Med Chem Lett. 2023 Jun 13;14(7):986-992. doi: 10.1021/acsmedchemlett.3c00175. eCollection 2023 Jul 13.

Authors

James J Perkins¹, Paul McQuade², Christopher J Bungard¹, Tracy L Diamond³, Liza T Gantert², Anthony L Gotter⁴, Barbara Hanney¹, Ivory D Hills¹, Danielle M Hurzy¹, Aniket Joshi², Jonathan T Kern⁴, Kelly-Ann S Schlegel¹, Jesse J Manikowski¹, Zhaoyang Meng¹, Julie A O'Brien³, Anthony J Roecker¹, Sean M Smith⁴, Jason M Uslaner⁴, Eric Hostetler², Robert S Meissner¹

Affiliations

¹ Departments of Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, USA.
² Translational Imaging, Merck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, USA.
³ Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, USA.
⁴ Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, USA.

Abstract

Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR₂ NAM) led to a series of analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer with convenient chemical handles for incorporation of a ¹¹C or ¹⁸F radiolabel. [¹¹C]MK-8056 was synthesized and evaluated in vivo and demonstrated appropriate affinity, selectivity, and physicochemical properties to be used as a positron emission tomography tracer for mGluR₂.