Click chemistry : radiolabelling of oligonucleotides with fluorine- 18 for PET

Oligonucleotides (ONs), especially small interfering RNA (siRNA), are promising therapeutic agents,
but their pharmacokinetics and biodistributions are widely unknown. Positron Emission Tomography
(PET) using fluorine-18 is a suitable technique to image and quantify such biological processes. The
challenge for the radiochemist is to introduce this short half-life isotope (t1/2(18F)=109.7 min) onto
oligonucleotides or, more generally, biomolecules. The most common technique requires the coupling
of a prosthetic group bearing the radiotracer with the biomolecule.
Current methods for labeling ONs with fluorine-18 have sub-optimal yields and require a long
synthesis time.1 Click chemistry, e.g. 1,3-dipolar Huisgen cycloaddition of azides to alkynes, could be
an efficient way to increase yields and reduce synthesis time.
Conjugations with ONs are usually performed at 3’-ends using a well-chosen linker in order to limit
degradation by exonucleases and to avoid alteration of hybridization properties and siRNA gene
silencing efficiency. This also allows the development of universal solid supports used for the solidphase
synthesis of ONs.
Here we report the synthesis of three alkyne-bearing linkers , the synthesis and
radiosynthesis of the complementary azido-bearing prosthetic groups (1-(azidomethyl)-4-[18F]-
fluorobenzene) and coupling with functionalized ONs.