Synthesis of a 11C-labelled Taxane Derivative by [1-11C]Acetylation


Synthesis of a 11C-labelled Taxane Derivative by [1-11C]Acetylation

Mäding, P.; Zessin, J.; Pleiß, U.; Wüst, F.

Taxans are an important class of antitumor agents. These compounds bind to the microtubuli and inhibit their depolymerization into tubulin. Subsequently, the mitosis is disrupted and the cells are not able to divide into daughter cells. Investigations with positron emission tomography (PET) are an important tool to determine the in vivo distribution and the pharmacokinetics of such drugs if they are labelled with positron-emitting radionuclides. This report describes the 11C-labelling of a taxan derivative as a new potent anticancer drug 1.
The acetyl moiety of 1 in position 10 was chosen to introduce carbon-11, because it is considered to be stable with respect to drug metabolism. For synthesis of the required precursor 2 the taxan 1 was selectively deacetylated in position 10 by treatment with sodium hydrogencarbonate and hydrogen peroxide. To avoid the known epimerization of the hydroxy group in position 7 and to stabilize the ester function in position 13 the 2’ and 7 hydroxy groups were protected with triethylsilyl moieties yielding the precursor 2.
[11C]1 was synthesized in a multi-step procedure according to the Scheme using an automated syn-thesis module. The capability of this module includes the radiosynthesis of [1﷓11C]acetyl chloride (3) and its conversion with the precursor 2 to an intermediate, which was hydrolysed to [11C]1, the HPLC purification of the final product, its solid phase extraction and formulation.
The used module was a commercially available module for 11C methylation from GE Medical Sys-tems (former Nuclear Interface), Münster, Germany.
[1﷓11C]Acetyl chloride (3) was synthesized by conversion of [11C]carbon dioxide with methyl-magnesium bromide in diethyl ether followed by quenching the resulting [11C]acetate solution with phthaloyl dichloride. After evaporation of the solvent, 3 was driven into a cooled THF solution of 2 and lithium hexamethyldisilazide. The [11C]acetylation took place at room temperature within 6 min. The solvent was evaporated and the residue was treated with a solution of hydrochloric acid in MeOH/dioxane for cleavage of the triethylsilyl protecting groups at room temperature. The crude product was purified by semipreparative RP HPLC and solid phase extraction at an RP﷓18-cartridge. The resulting ethanolic solution of [11C]1 and a saline solution was transferred succes-sively through a sterile filter to obtain the final formulation of [11C]1. The decay-corrected radio-chemical yields were in the range of 6 to 19 % (related to [11C]CO2) within a synthesis time of 45-50 min. The radiochemical purity exceeded 96 %, the chemical purity was in the range of 80-99 %.
The specific radioactivity of the final product was up to 18 GBq/µmol at 11 successful attempts with starting radioactivities of 26 GBq.

Keywords: taxan; anticancer drug; [1-11C11]acetyl chloride; automated module synthesis; PET

  • Lecture (Conference)
    11th Conference of the Central European Division e. V. of the International Isotope Society, Bad Soden, 25.-26.09.2003
  • Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 47(2004), 263-265

Permalink: https://www.hzdr.de/publications/Publ-5681
Publ.-Id: 5681