Sugar Amino Acid Linkers for the Design of [¹⁸F]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 ¹⁸F-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 (IC₅₀ = 5-19 µM), while pyranose-SAA analogues 23 and 24 were inactive (IC₅₀ > 100 µM). All compounds exhibited similar lipophilicity (logP = 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 [¹⁸F]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.