Arginine-Selective Bioconjugation Reagent for Effective ¹⁸F‑labeling of Native Proteins

Protein-based ¹⁸F-PET tracers offer new possibilities in early disease detection and personalized medicine. Their development relies heavily on the availability and effectiveness of ¹⁸F-prosthetic groups. We prepared and evaluated a novel arginine-selective prosthetic group, 4-[¹⁸F]fluorophenylglyoxal ([¹⁸F]FPG). [¹⁸F]FPG was radiosynthesized by a one-pot, two-step procedure with a non-decay-corrected (n.d.c.) isolated radiochemical yield (RCY) of 41 ± 8% (n = 10). [¹⁸F]FPG constitutes a generic tool for ¹⁸F-labeling of various proteins, including human serum albumin (HSA), ubiquitin, interleukin-2, and interleukin-4 in ∼30–60% n.d.c. isolated RCYs. [¹⁸F]FPG conjugation with arginine residues is highly selective, even in the presence of a large excess of lysine, cysteine, and histidine. [¹⁸F]FPG protein conjugates are able to preserve the binding affinity of the native proteins while also demonstrating excellent in vivo stability. The [¹⁸F]FPG-HSA conjugate has prolonged blood retention, which can be applied as a potential blood pool PET imaging agent. Thus, [¹⁸F]FPG is an arginine-selective bioconjugation reagent that can be effectively used for the development of ¹⁸F-labeled protein radiopharmaceuticals.