PT - JOURNAL ARTICLE AU - Li, Zizhong AU - Hagiwara, Hiroaki AU - Takaishi, Mamoru AU - Teceno, Tyler AU - Krause, Stephen AU - sasaki, Takeo AU - McCracken, Paul AU - Koyama, Akihiko AU - Terauchi, Taro TI - Discovery of a New Class of mGluR2 Selective Group II mGluR NAM PET Tracer DP - 2017 May 01 TA - Journal of Nuclear Medicine PG - 548--548 VI - 58 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/58/supplement_1/548.short 4100 - http://jnm.snmjournals.org/content/58/supplement_1/548.full SO - J Nucl Med2017 May 01; 58 AB - 548Objectives: Metabotropic glutamate receptor subtype 2 (mGluR2) and metabotropic glutamate receptor subtype 3 (mGluR3) are the two members of Group II mGluRs. The mGluR2 is predominately distributed in pre-synaptic neurons. mGluR2 modulates synaptic glutamate release through a feedback mechanism. Activation of mGluR2 decreases glutamatergic transmission in the synapse and produces a cognitive impairment; inhibition of mGluR2 improves acquisition of spatial learning, indicating mGluR2 is an attractive target to develop symptomatic treatment and/or disease modifier for Alzheimer’s disease. Eisai has a Group II mGluR medicinal chemistry program aimed at developing Group II mGluR negative allosteric modulator (NAM) applicable as a therapeutic agent for neurological disorders related to glutamate dysfunction and diseases involving the mGluR2. The specific aims of this study were to develop a Group II mGluR NAM PET tracer with high mGluR2 selectivity for the measurement of mGluR2 availability and the assessment of Group II mGluR NAM drug candidate mGluR2 receptor occupancy in vivo.Methods: A series of potent Group II mGluR NAM were labeled with fluorine-18. [18F]ER-000604699 demonstrated satisfactory pharmacokinetics properties, brain uptake, and specific binding in the brain of rat and marmoset, which warrants further evaluation in human. The F-18 labeled compounds ([18F]ER-000604699 to [18F]5) were synthesized from their corresponding tosylates (6 to 10) through a nucleophilic substitute reaction with [18F] fluoride in acetonitrile with a microfluidic synthesis platform (Advion, NanoTek®). The radiochemical yield (RCY) at EOS for [18F]ER-000604699 is 19.1 % ± 5.1% (n = 12, decay no-corrected); the specific activity is 0.702 ± 0.146 Ci/µmol (n = 12). Compound [18F]ER-000604699 to [18F]5 were evaluated with PET (NanoScan, Mediso) and in vitro and ex vivo autoradiography.Results: Comparison of autoradiography of [18F]ER-000604699 with that of [3H]LY459477 in transgenic mice lacking either mGluR2, mGluR3 or both (Neuropharmacology 66 (2013) 89-98), we concluded that [18F]ER-000604699 showed specific binding in accordance with the overall distribution of Group II mGluR with high mGluR2 selectivity in rodent brain. Small animal PET studies in rat and marmoset demonstrated that [18F]ER-000604699 binds specifically and reversibly to Group II mGluR allosteric sites, with highest uptake in the caudate-putamen, the cortex, and the hippocampus, and lowest in the medulla. The medulla was used as a reference region, and Logan Graphic Analysis was used to quantify receptor availability and tracer-receptor interaction in the brain. A comparison of binding potential (BPND) in different brain regions showed that the Group II mGluR expression in the brain is species dependent from rodent to the marmoset. The binding of [18F]ER-000604699 in the brain of rat and marmoset was blocked with ER-000602792 in a dose-dependent manner; ER-000602792 is a potent Group II mGluR NAM from the same chemical scaffold. An Emax modeling results indicated that ER-000602792 target exposure does not appear to be species dependent from rodent to marmoset.Conclusion: A new class of Group II mGluR NAM PET tracer with high mGluR2 selectivity was discovered. The utility of [18F]ER-000604699 for measuring mGluR2 availability at baseline and after Group II mGluR NAM treatment has been demonstrated Research Support: This research was supported by Eisai Inc