title: Inhibition of radical reactions for an improved potassium tert-butoxide-promoted (11) C-methylation strategy for the synthesis of α-(11) C-methyl amino acids.
abstract: α-(11) C-Methyl amino acids are useful tools for biological imaging studies. However, a robust procedure for the labeling of amino acids has not yet been established. In this study, the (11) C-methylation of Schiff-base-activated α-amino acid derivatives has been optimized for the radiosynthesis of various α-(11) C-methyl amino acids. The benzophenone imine analog of methyl 2-amino butyrate was (11) C-methylated with [(11) C]methyl iodide following its initial deprotonation with potassium tert-butoxide (KOtBu). The use of an alternative base such as tetrabutylammonium fluoride, triethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene did not result in the (11) C-methylated product. Furthermore, the KOtBu-promoted (11) C-methylation of the Schiff-base-activated amino acid analog was enhanced by the addition of 1,2,4,5-tetramethoxybenzene or 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and inhibited by the addition of 1,10-phenanthroline. These results suggest that inhibition of radical generation induced by KOtBu improves the α-(11) C-methylation of the Schiff-base-activated amino acids. The addition of a mixture of KOtBu and TEMPO to a solution of Schiff-base-activated amino acid ester and [(11) C]methyl iodide provided optimal results, and the tert-butyl ester and benzophenone imine groups could be readily hydrolyzed to give the desired α-(11) C-methyl amino acids with a high radiochemical conversion. This strategy could be readily applied to the synthesis of other α-(11) C-methyl amino acids.
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan; Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Suzuki
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D000440:Butanols / Q000737:chemistry*; D002250:Carbon Radioisotopes / Q000737:chemistry*; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D005609:Free Radicals / Q000737:chemistry; D008745:Methylation; D011854:Radiochemistry; D012545:Schiff Bases / Q000737:chemistry
chemical_list: D000596:Amino Acids; D000440:Butanols; D002250:Carbon Radioisotopes; D005609:Free Radicals; D012545:Schiff Bases; C077664:tert-butoxide, potassium
keywords: PET; Schiff base; amino acid; electron transfer; potassium tert-butoxide; radical; α-methylation