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Background: As the most important excitatory neurotransmitter in the mammalian central nervous system (CNS), glutamate mediates synaptic plasticity, neurodevelopment, memory and its dysfunction has been associated with multiple neurodegenerative diseases and neurological disorders. Metabotropic glutamate receptors (mGluRs), which belong to family C G-protein-coupled receptors (GPCRs), are widely expressed in neuronal cells. Type 7 metabotropic glutamate receptors (mGluR7), one of Group III mGluRs (mGluR4, mGluR6-8), is mainly located in the brain regions that are associated with reward, cognition and emotion. Increasing research attention has been made for further understanding of the potential role of mGluR7 in the pathophysiology of CNS disorders. This study was aimed to develop a mGluR7 radioligand for PET neuroimaging. Methods: Based on the structure of the first and only reported mGluR7 selected radioligand [11C]MMPIP, a methoxy analog MG7-2109 was designed and synthesized. While pharmacological properties were investigated with nonradiolabeled compound, further biological evaluations were carried out by logD study and in vitro radiometabolism studies with carbon-11 labeled [11C]MG7-2109. Results: Target compound and the corresponding precursor were efficiently synthesized with 6% and 2% overall yields in 7 and 8 steps, respectively (Scheme 1A). Starting with 3-methoxybenzaldehyde, oxime intermediate was produced and then reacted with N-chlorosuccinimide to form Cl-substituted oxime. Target compound was then obtained through subsequently intermolecular and intramolecular cyclization, while the corresponding precursor was generated from demethylation of target compound using BBr3. The potency of MG7-2109 was determined in GIRK functional assays and showed to be 81 nM (versus MMPIP = 223 nM) as partial NAM or antagonist. [11C]MG7-2109 was synthesized in radiochemical yields of 11.5% in 35 min with more than 99% radiochemical purity (Scheme 1B). LogD value through the ‘shake flask’ method was determined to be 3.39±0.02, demonstrating a high probability for BBB permeability. In addition, excellent stability was found in in vitro serum stability studies in different species, including mice, rats, nonhuman primates and humans (94%, 98%, 98% and 98% of intact parent at 30 min, respectively). Conclusion: In this study, we have successfully synthesized a mGluR7-targeted radioligand [11C]MG7-2109, followed by preliminary in vitro evaluation. Further evaluation by ex vivo and in vivo studies in rodents will be reported in due course. |
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