@misc{oai:repo.qst.go.jp:00086445,
 author = {Xiao, Zhiwei and Sun, Jiyun and Zhao, Chunyu and Haider, Ahmed Haider, Ahmed and Rong, Jian and J. Sheffler, Douglas and Cosford, Nicholas and Zhang, Ming-Rong and Liang, Steven and Zhang, Ming-Rong},
 month = {Jun},
 note = {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},
 title = {Synthesis and preclinical evaluation of a carbon-11 labeled metabotropic glutamate receptor 7 radioligand},
 year = {2022}
}