Stability of fluorotrialkylsilanes as prosthetic groups for instant labelling of biomolecules with fluorine-18

Background: Current methods for 18F labelling of peptides for PET imaging are time-consuming and complex. More efficient (preferably single step) methods, analogous to 99mTc kits, are required because of the short half-life (110 min) of 18F. It has been suggested [1] that single-step nucleophilic fluorination with fluoride ions may be possible using silicon-fluorine chemistry.

Aims: This work aims to identify suitable alkyl groups to include in the required alkoxytrialkylsilane, in order to achieve the fastest radiolabelling nucleophilic displacement of alkoxide by fluoride) and optimal kinetic stability of the Si-F bond (and hence optimal in vivo stability).

Material & Methods: Four model trialkylfluorosilanes were synthesised and evaluated using HPLC and NMR to determine rates of formation and hydrolysis of Si-F bonds: ButPh2SiF, Ph3SiF, ButMe2SiF, and Me2PhSiF. The fluorosilanes were incubated in 1:1 phosphate buffered saline (pH 7.4):acetonitrile solution, and in 1:1 acetate buffer (pH 5):acetonitrile, 1:1 bicarbonate buffer (pH 8.5 and 11).

Results: Rapid Si-F bond formation (within 5 minutes at 40oC) on reaction of trialkylalkoxysilanes with fluoride was confirmed by NMR and HPLC in all cases, showing that rapid fluorination is feasible. However, only ButPh2SiF showed sufficient hydrolytic stability at 40oC to allow feasibility of imaging studies. At pHs 5 and 7.5 hydrolysis of ButPh2SiF was not detectable even at 6 h. In alkaline conditions its hydrolysis was more rapid: at pH 8.5 it was below 15% at 2 h, and at pH 11 it was complete before 1.75 h.

Conclusion: The hydrolysis of the Si-F bond to give a hydroxysilane and fluoride is base-catalysed but is slow at acidic, neutral and mildly basic pH. The rate of Si-F bond formation from alkoxysilane is fast enough for radiolabelling within a few minutes. Steric hindrance is a requirement to ensure adequate kinetic stability of the Si-F bond, and the t-butyldiphenylalkoxysilane group has therefore been selected for further development as a prosthetic group for single step labeling with 18F- ions straight from the cyclotron.