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

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

James J Perkins  1 , Paul McQuade  2 , Christopher J Bungard  1 , Tracy L Diamond  3 , Liza T Gantert  2 , Anthony L Gotter  4 , Barbara Hanney  1 , Ivory D Hills  1 , Danielle M Hurzy  1 , Aniket Joshi  2 , Jonathan T Kern  4 , Kelly-Ann S Schlegel  1 , Jesse J Manikowski  1 , Zhaoyang Meng  1 , Julie A O'Brien  3 , Anthony J Roecker  1 , Sean M Smith  4 , Jason M Uslaner  4 , Eric Hostetler  2 , Robert S Meissner  1
Affiliations

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

James J Perkins et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
In vitro profile of compound 1.
Scheme 1
Scheme 1. Synthesis of [11C]22
Reagents and conditions: a3-Chloroperoxybenzoic acid, dichloromethane, 85%. Dimethylcarbamyl chloride, trimethylsilyl cyanide, dichloromethane, reflux, 70%. (2-Fluoro-4-methoxyphenyl)boronic acid, 2 M sodium carbonate, Pd(PPh3)4, toluene/ethanol, 75° C, 52%. Sat HCl/MeOH, 60° C, 90%. Potassium vinyl trifluoroborate, Pd(OAc)2, S-Phos, Cs2CO3, water/dioxane, 85° C, 71%. 9-BBN, THF, 60° C, then 5-bromo-2-methylpyrimidine, (X-Phos) palladium(II) phenethylamine chloride, K2CO3, water/THF, 90° C, 50%. 7 M NH3/MeOH, 60 °C, 100%. BBr3, dichloromethane, 0 to 25 °C, 37%. [11C]Methyl iodide, Cs2CO3, DMF, 0 to 70 °C.
Figure 2
Figure 2
Coregistered sagittal PET/MRI summed image (0–90 min) of [11C]22 in rhesus monkey brain: (left panel) baseline data; (right panel) data obtained post administration of MK-8768. The scale is shown in standardized uptake value (SUV) units, which are normalized for the injected radioactive dose and the mass of the monkey. Ctx = cortex; Cb = cerebellum; WM = white matter; Th = thalamus; and St = striatum.
See this image and copyright information in PMC

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