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

Org Biomol Chem. 2011 Jun 7;9(11):4287-94. doi: 10.1039/c0ob01249a. Epub 2011 Apr 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Chromatography, High Pressure Liquid
  • Humans
  • Methylation
  • Molecular Structure
  • Nucleosides* / chemical synthesis
  • Nucleosides* / chemistry
  • Organometallic Compounds / chemistry*
  • Palladium / chemistry*
  • Stereoisomerism
  • Thymidine / analogs & derivatives*
  • Thymidine / chemistry
  • Tomography, Emission-Computed*

Substances

  • Nucleosides
  • Organometallic Compounds
  • Palladium
  • Thymidine