Presentation 「Synthesis of [11C]ADX88178 via C-[11C]methylation with [11C]CH3I as a PET ligand for imaging of the metabotropic glutamate 4 receptor」

Fujinaga, Masayuki  ,  Yamasaki, Tomoteru  ,  Yui, Joji  ,  Xie, Lin  ,  Nengaki, Nobuki  ,  Hatori, Akiko  ,  Kumata, Katsushi  ,  Shimoda, Yoko  ,  Kawamura, Kazunori  ,  Ming-Rong, Zhang

2015-05-31
Description
Objectives: Metabotropic glutamate receptors (mGlus) are one of the G protein-coupled receptor families, whichregulate excitatory neurotransmissions on central nerves system. Of these, mGlu4 which together with mGlu6-mGlu8receptors belongs to group III has received a lot of attention because of the potential therapeutic effect by mGlu4activation in several diseases such as Parkinson’s disease. However, to-date no appropriate mGlu4 PET ligand hasbeen employed. Recently, Le Poul et al. has developed ADX88178 as a potent and selective ligand for mGlu4 [1]. C-[11C]methylation of pyrimidine ring at 2- or 6-position has not been previously reported. In this study, we report thesynthesis of [11C]ADX88178 via incorporation of 11CH3 group into pyrimidine ring at 6-position.Methods: ADX88178 was prepared at 8 steps from ethyl 4-pyrazolecarboxylate. Synthesis of [11C]ADX88178 wasperformed by C-[11C]methylation reaction of 2 with [11C]CH3I, followed by deprotection of p-methoxybenzyl group in [11C]1 with trifluoroacetic acid.Results: C-[11C]methylation of 2 with [11C]CH3I in the presence of Pd2(dba)3, P(o-tol)3, CuCl, and K2CO3 at 80oC for 5 min only produced [11C]1 in 40% yield, which was determined by analyzing the reaction mixture using radio-HPLC. Instead of K2CO3, using CsF as a base, the C-[11C]methylation yield was improved up to 90%. After the [11C]methylation and removal of DMF, debenzylation of [11C]1 with TFA at 100oC for 5 min and purification for thereaction mixture using semi-preparative HPLC gave [11C]ADX88178 in 3 % radiochemical yield (based on the total [11C]CO2, corrected for decay). Starting from 22 GBq of [11C]CO2, 0.13 GBq of [11C]ADX88178 was produced within43 min of synthesis time from EOB. In the final product solution, the radiochemical purity of [11C]ADX88178 was >98%.Conclusions: We succeeded in the synthesis of [11C]ADX88178 by 2 step reactions of C-11C coupling and debenzylation. This novel PET ligand is now available for evaluation in mice or rat and improvement for theradiochemical yield is on progress.References: [1] Emmanuel L. P, et al (2012), J. Pharm. Exp. Ther., 343, 167-177.
21st International Symposium on Radiopharmaceutical Sciences

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