title: Highly efficient syntheses of [methyl-11C]thymidine and its analogue 4'-[methyl-11C]thiothymidine as nucleoside PET probes for cancer cell proliferation by Pd(0)-mediated rapid C-[11C]methylation.
abstract: Pd(0)-mediated rapid couplings of CH(3)I (and then [(11)C]CH(3)I) with excess 5-tributylstannyl-2'-deoxyuridine and -4'-thio-2'-deoxyuridine were investigated for the syntheses of [methyl-(11)C]thymidine and its stable analogue, 4'-[methyl-(11)C]thiothymidine as PET probes for cancer diagnosis. The previously reported conditions were attempted using Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3) (1 : 4 in molar ratio) at 130 °C for 5 min in DMF, giving desired products only in 32 and 30% yields. Therefore, we adapted the current reaction conditions developed in our laboratory for heteroaromatic compounds. The reaction using CH(3)I/stannane/Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3)/CuCl/K(2)CO(3) (1 : 25 : 1 : 32 : 2 : 5) at 80 °C gave thymidine in 85% yield. Whereas, CH(3)I/stannane/Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3)/CuBr/CsF (1 : 25 : 1 : 32 : 2 : 5) including another CuBr/CsF system promoted the reaction at a milder temperature (60 °C), giving thymidine in 100% yield. Chemo-response of thiothymidine-precursor was different from thymidine system. Thus, the above optimized conditions including CuBr/CsF system gave 4'-thiothymidine only in 40% yield. The reaction using 5-fold amount of CuBr/CsF at 80 °C gave much higher yield (83%), but unexpectedly, the reaction was accompanied by a considerable amount of undesired destannylated product. Such destannylation was greatly suppressed by changing to a CuCl/K(2)CO(3) system using CH(3)I/stannane/Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3)/CuCl/K(2)CO(3) (1 : 25 : 1 : 32 : 2 : 5) at 80 °C, giving the 4'-thiothymidine in 98% yield. The each optimized conditions were successfully applied to the syntheses of the corresponding PET probes in 87 and 93% HPLC analytical yields. [(11)C]Compounds were isolated by preparative HPLC after the reaction conducted under slightly improved conditions, exhibiting sufficient radioactivity of 3.7-3.8 GBq and specific radioactivity of 89-200 GBq µmol(-1) with radiochemical purity of ≥99.5% for animal and human PET studies.
authors.affiliation: Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu, 501-1193, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Koyama
authors.lastname: Siqin
authors.forename: Zhouen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Kengo
authors.initials: K
authors.lastname: Sumi
authors.forename: Yuma
authors.initials: Y
authors.lastname: Hatta
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagata
authors.forename: Hisashi
authors.initials: H
authors.lastname: Doi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008745:Methylation; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry; D014055:Tomography, Emission-Computed
chemical_list: D009705:Nucleosides; D009942:Organometallic Compounds; D010165:Palladium; D013936:Thymidine