Optimization of the solid-phase synthesis of [18F] radiolabeled peptides for positron emission tomography

Establishing improved methods for the radiolabeling of peptides with fluorine-18 via solid-phase peptide synthesis (SPPS) is desirable for the efficient synthesis of peptide-based molecular imaging agents. This work focuses on the development of a standardized platform to facilitate the reliable and efficient synthesis of high-purity fluorine-18 radiolabeled peptides for in vivo imaging with positron emission tomography (PET). Seven commercially available resins were selected for solid-phase radiolabeling of the model peptide VQAAIDYING with 4-[18F]fluorobenzoic acid ([18F]FBA). A wide range of radiochemical yields (18.8±1.5% to 41.2±5.3%) was obtained using standard conditions (coupling: 3 eq amino acid, 3 eq HATU, 6 eq DIPEA, 1.5 h, r.t.; cleavage: 94% TFA, 3 h, r.t.). After modification of coupling reagents and employing heated reactions to 37 °C, radiochemical yields were improved by as much as 35.3% over standard conditions. When the optimized conditions were applied to the synthesis of [18F]FBA-PEG28-A20FMDV2, which targets the αvβ6 integrin in vivo, radiochemical yields improved by as much as 73.4% over those obtained using standard coupling and cleavage conditions. This platform can be utilized to improve the synthesis of peptide-based molecular probes for molecular imaging with PET.

► Optimization of solid-phase radiolabeling is dependent on resin selection.
► Developed an improved method for solid-phase peptide radiolabeling with [18F]FBA.
► Optimized conditions improved radiochemical yields of control peptide by 35.3%.
► Radiochemical yields of [18F]FBA-PEG28-A20FMDV2 peptide increased by 73.4%.