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Purpose/Background: Glutamate, as the primary excitatory neurotransmitter in the mammalian central nervous system (CNS), plays a vital role in fundamental brain functions, involving synaptic plasticity, neurodevelopment. Accordingly, metabotropic glutamate receptors (mGluRs) are widely expressed in CNS and modulate neuronal excitability and synaptic transmission. In Group III mGluRs (mGluR4, 6-8), type 7 metabotropic glutamate receptors (mGluR7) are distinctively expressed at presynaptic active zone and would be only activated by glutamate release. Furthermore, mGluR7 is highly expressed in brain regions that are associated with reward, cognition and emotion functions. Therefore, this study was aimed to develop a mGluR7 radioligand and provide better understanding of mGluR7 in vivo under pathophysiological conditions of CNS disorders. Methods: MG7-2019 and corresponding precursor were designed and synthesized on the basis of structure of [11C]MMPIP, the first and only reported mGluR7 selected radioligand. Biological evaluations of [11C]MG7-2109 were carried by logD measurement, in vitro radiometabolism studies, ex vivo biodistribution studies and in vivo PET imaging studies. Results: MG7-2109 and the corresponding precursor were efficiently synthesized in 6% and 2% overall yields, respectively. [11C]MG7-2109 was obtained in more than 99% radiochemical purity with radiochemical yields of 11.5% in 35 min (Figure 1A). Through the ‘shake flask’ method, LogD value was determined to be 3.39±0.02. Parent tracer was proved to be stable at 30 min in in vitro serum stability studies from mice (94%), rats (98%), non-human primate (98%) and human (98%), respectively, demonstrating its excellent in vitro stability. Whole body ex vivo biodistribution studies in CD-1 mice showed high uptake (ID%/g > 3) in brain, heart and lung at 5 min p.i., followed with gradual clearance in next 60 min (Figure 1B). The high uptake in small intestine (> 20 %ID/g) and liver (>10 %ID%/g) indicated a hepatobiliary clearance pathway of [11C]MG7-2109. Heterogeneous brain uptake was demonstrated in PET imaging studies in rat brain, with the highest tracer uptake observed in the striatum and thalamus, followed by hippocampus and cerebellum (Figure 1C). Conclusion: In this study, we have successfully synthesized a mGluR7-targeted radioligand [11C]MG7-2109 and performed preliminary evaluation in rodents. Further evaluation by blocking PET imaging studies in rodent and higher species will be reported in due course., SNMMI2022

Metabotropic glutamate receptor 2 (mGlu2) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu2, we identified new candidates 5a–i that are potent negative allosteric modulators (NAMs) of mGlu2. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as [11C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 (11C) to obtain [11C]5i in high radiochemical yield and high molar activity by O-[11C]methylation of the phenol precursor 12 with [11C]CH3I. In vitro autoradiography with [11C]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [11C]5i indicated in vivo specific binding of mGlu2 in the rat brain. Based on the [11C]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu2.

Selective modulation of metabotropic glutamate receptor 2 (mGlu2) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson’s disease (PD), Alzheimer’s disease (AD), drug abuse and addiction. Imaging mGlu2 using positron emission tomography (PET) would allow in vivo quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. However, to date, few successful efforts have been disclosed to visualize mGlu2 in vivo, indicating an unmet and urgent clinical need. Herein we report the synthesis and preclinical evaluation of a focused library of mGlu2 modulators amenable for radiolabeling. The promising candidate 4-(2,4-difluorophenyl)-7-((2-methoxypyridin -4-yl)methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxamide (21b), exhibited high potency and excellent subtype selectivity, which was then evaluated by in vitro autoradiography and in vivo PET imaging studies after labeling with carbon-11. Ligand [11C]21b (also known as [11C]MG2-1904) demonstrated high brain uptake and excellent in vitro/in vivo specific binding towards mGlu2 with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu2 in vivo derived from negative allosteric modulators (NAMs), which represents a promising chemotype for further development and optimization aimed for clinical translation.

Metabotropic glutamate 2 receptors (mGlu2) are involved in the pathogenesis of several CNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents a potential disease-modifying approach for the treatment of substance abuse, depression, schizophrenia and dementias. While quantification of mGlu2 receptors in the living brain by positron emission tomography (PET) would help us better understand signaling pathways relevant to these conditions, few successful examples have been demonstrated to image mGlu2 in vivo and a suitable PET tracer is yet to be identified. Herein we report the design and synthesis of a radiolabeled negative allosteric modulator (NAM) for mGlu2 PET tracer development based on a quinoline 2-carboxamide scaffold. The most promising candidate, 7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4- [11C]methoxyphenyl) quinoline-2-carboxamide ([11C]QCA) was prepared in 13% radiochemical yield (non-decay corrected at the end of synthesis) with >99% radiochemical purity and >74 GBq/μmol (2 Ci/μmol) specific activity. While the tracer showed limited brain uptake (0.3 SUV), probably attributable to effects on PgP/Bcrp eff lux pump, in vitro autoradiography studies demonstrated heterogeneous brain distribution and specific binding. Thus, [11C]QCA is a chemical probe that