Synthesis of 18F-labeled stilbenes from 4-(18F)fluorobenzaldehyde using the Horner-Wadsworth-Emmons reaction

Introduction:

The coupling of phosphonic acid esters with carbonyl compounds, also referred to as the Horner-Wadsworth-Emmons reaction, represents a powerful carbonyl olefination reaction to form C-C double bonds, exhibiting E-configuration exclusively.
This work describes the application of the Horner-Wadsworth-Emmons reaction as novel labeling technique in 18F-chemistry. Various 18F-labeled E-configured stilbenes could be synthesized through the coupling of benzylic phosphonic acid esters with readily available 4-[18F]fluorobenzaldehyde 1 as labeling precursor (Fig. 1).

Experimental:

The carbonyl-olefination reaction was performed via a “multi-step/one-pot” reaction by the coupling of benzylic phosphonic acid esters (3,5-bis-methoxymethoxybenzyl)-phosphonic acid diethyl ester 2a, (4-methoxymethoxybenzyl)-phosphonic acid diethyl ester 3a and (4-dimethyl-aminobenzyl)phosphonic acid diethyl ester 4a) with 4-[18F]fluorobenzaldehyde to give the corresponding 18F-labeled stilbenes [18F]2b, [18F]3b and [18F]4b exclusively as the expected E-isomers after deprotection. The radiochemical yields ranged from 9 to 22% (based upon [18F]fluoride, including HPLC purification). The specific activity reached up to 90 GBq/μmol.

Results and Discussion:

The reaction can be applied for the synthesis of polyphenolic compounds and aromatic amines bearing an E-configured stilbene backbone as pharmaceutically interesting compounds. Several E-configured stilbene-based polyphenols are known to be potential anticancer compounds. In the case of amine group-containing stilbene compound [18F]4b, structural comparable stilbenes have been reported as potential ligands to bind to Aβ-plaques found in the brain of patients with the neurodegenerative Alzheimer's disease. Preliminary radiopharmacological studies including small animal PET of compound [18F]4b in normal rats showed promising brain uptake. Results on the radiopharmacological characterization of compound [18F]4b will be presented.

Conclusion:

The described method opens a convenient access to a large number of 18F-labeled compounds bearing an E-configured stilbene backbone.

Acknowledgement: The authors wish to thank S. Preusche for radioisotope production and T. Krauss for technical assistance.