Sugar Amino Acid Linkers for the Design of [ ¹⁸ F]SiFA‐PSMA Radioligands

The pronounced lipophilicity of tert ‐butyl‐substituted silicon‐fluoride‐acceptor (SiFA) scaffolds represents a major limitation in radiotracer development, often resulting in elevated nonspecific uptake and reduced tumor‐to‐background ratios. To address this challenge, we designed and synthesized a series of prostate‐specific membrane antigen (PSMA)‐targeted radioligands incorporating furanose‐ and pyranose‐based sugar amino acid (SAA) linkers to evaluate physicochemical properties while maintaining efficient ¹⁸ F‐radiolabeling capability. Six compounds ( 19 –24 ) were prepared via a convergent three‐step synthesis in 35%–75% overall yield. Furanose‐SAA derivatives ( 19–22 ) retained moderate PSMA binding affinity (IC ₅₀  = 5–19 µM), while pyranose‐SAA analogues 23 and 24 were inactive (IC ₅₀  > 100 µM). All compounds exhibited similar lipophilicity (log P = 3.10–3.42), indicating that the differences in biological activity are not primarily attributable to lipophilicity. Compounds 19 and 21 were radiolabeled via isotopic exchange in 25%–40% radiochemical yield with molar activity of 86 ± 3 GBq/µmol. PET imaging in LNCaP xenograft mice demonstrated that [ ¹⁸ F]21 , bearing three furanose‐SAA units, achieved SUV _60min  = 0.64 ± 0.06 with  ~30% blocking by DCFPyL, confirming partial PSMA‐mediated uptake. This proof‐of‐concept study establishes SAA linkers as a viable strategy for pharmacokinetic optimization of SiFA‐based radiotracers, warranting further structural refinement to enhance target affinity.