@misc{oai:repo.qst.go.jp:00071870,
 author = {Fujinaga, Masayuki and Yamasaki, Tomoteru and Nengaki, Nobuki and Ogawa, Masanao and Kumata, Katsushi and Shimoda, Yoko and Yui, Joji and Xie, Lin and Zhang, Yiding and Kawamura, Kazunori and Zhang, Ming-Rong and 藤永 雅之 and 山崎 友照 and 念垣 信樹 and 小川 政直 and 熊田 勝志 and 下田 陽子 and 由井 譲二 and 謝 琳 and 張 一鼎 and 河村 和紀 and 張 明栄},
 month = {Nov},
 note = {Objectives:  Metabotropic glutamate receptors (mGluRs) are one of the G protein-coupled receptor families, which regulate excitatory neurotransmissions on the central nerves system (CNS). Of these, mGluR4 has received particular attention because of the potential therapeutic effect by mGluR4 activation in several CNS disorders. For example, several pharmaceuticals for mGluR4 were reported to show neuroprotective activity in models of Parkinson’s disease, a degenerative disorder of dopaminergic neurons in the basal ganglia. However, to-date no appropriate mGluR4 PET ligand has been employed. Recently, ADX88178 (1) has been developed as a selective and potent positive allosteric modulator for metabotropic glutamate receptor 41). To the best of our knowledge, [11C]methylation of pyrimidine ring at 4- or 6-position has not been previously reported. The aim of this study was to challenge the introduction of [11C]methyl group into pyrimidine ring and develop [11C]1 as a novel PET ligand for mGluR4.
Results and Discussion:  Compound 5 was prepared from ethyl 4-pyrazolecarboxylate at 6 steps as described previously2). After deprotection of 5 with TFA, N-arylation reaction of thiazole derivatives 5 or 6 with 2-bromo-4-substituted pyrimidines in the presence of Pd(OAc)2/Xanthophos afforded 2, 3, or 4 in moderate yields. Compound 1 was synthesized by debenzylation of 2 with TFA. 
Synthesis of [11C]1 was performed via C-[11C]methylation reaction by using of two precursor. Firstly, C-[11C]methylation of heteroarylstannane 4 was performed with [11C]CH3I in the presence of Pd2(dba)3, P(o-tol)3, CuCl, and base at 80 oC for 5 min. When K2CO3 or CsF were used as a base, only trace [11C]1 was produced and unreacted [11C]CH3I was mainly observed. On the other hand, when C-[11C]methylation of heteroarylstannane 3 was smoothly proceeded in the presence of CsF as a base. However, the following deletion of the PMB group in [11C]2 did not proceed by addition of TFA to the reaction mixture in DMF. When DMF was partly removed after [11C]-methylation, the deprotection with TFA produced a mixture of [11C]1 and [11C]2. To accomplish efficient deprotection of PMB in [11C]2, DMF was completely removed under reduced pressure after the C-11C coupling reaction. Finally, cleavage of the PMB group in [11C]2 proceeded efficiently in TFA at 100 oC for 5 min. Purification for the reaction mixtures using reversed phase semi-preparative HPLC gave [11C]1 in 16 ± 6% (n = 5) radiochemical yield at 2 steps (based on the total [11C]CO2, corrected for decay). Starting from 22 GBq of [11C]CO2, 0.54–1.10 GBq of [11C]1 was produced within 45 min of synthesis time from EOB. In the final product solutions, the radiochemical purity of [11C]1 was high than 98% and the purity remained >95% after 90 min.
 In vitro autoradiography was performed with [11C]1 using rat brain sections. In the control section, radioactivity signals were detected in the cerebellum, striatum, thalamus, cerebral cortex, and medulla oblongata. In addition, the radioactivity expression was decreased by treatment with unlabeled 1; a decrease of 12.3% for the cerebellum, 13.8% for the thalamus, 12.5% for the medulla oblongata, and 15.8% for the striatum. These distribution patterns of radioactivity in the control section were similar to the reported biological distribution pattern of mGluR4 in the rat brain. However, radioactivity was also seen in some mGluR4-negligible regions, such as the cerebral cortex and midbrain, suggesting that specific binding of [11C]1 may contain binding to other receptors.
Conclusions:  We successfully synthesized [11C]1 as a novel radioligand for mGluR4 by 2 step reaction with C-[11C]methylation and debenzylation reaction. This labeling technique enables synthesis of PET ligands including electron-deficient [11C]methylpyrimidine or pyridine moieties. [11C]1 showed specific binding for mGluR4 in the in vitro autoradiogram of rat brain, although the specific binding of [11C]1 was not so high. Therefore, development of new candidates with higher binding affinity to mGluR4 than 1 is required., Ninth Japan-China Joint Seminar on Radiopharmaceutical Chemistry},
 title = {Radiosynthesis of [11C]ADX88178 via direct [11C]methylation as a novel radioligand for imaging of  metabotropic glutamate receptor subtype 4},
 year = {2015}
}