Development of ¹⁸F‑Labeled Vinyl Sulfone–PSMAi Conjugates as New PET Agents for Prostate Cancer Imaging

Radiolabeled prostate-specific membrane antigen (PSMA) ligands have been rapidly adopted as part of patient care for prostate cancer. In this study, a new series of ¹⁸F-labeled PSMA-targeting agents was developed based on the high-affinity Glu-ureido-Lys scaffold and ¹⁸F-vinyl sulfones (VSs), the tumor uptake and tumor/major organ contrast of which could be tuned by pharmacokinetic linkers within the molecules. In particular, ¹⁸F-PEG₃-VS-PSMAi showed the highest tumor uptake (12.1 ± 2.2%ID/g at 0.5 h p.i.) and ¹⁸F-PEG₂-VS-PSMAi showed the highest tumor-to-liver ratio (T/L = 3.7 ± 1.0, 4.8 ± 1.2, and 6.3 ± 1.1 at 0.5, 1.5, and 3 h p.i. respectively). Significantly, compared with the FDA-approved ⁶⁸Ga-PSMA-11, the newly developed ¹⁸F-PEG₃-VS-PSMAi has an almost double tumor uptake (P < 0.0001) when tested in the same animal model. In conclusion, ¹⁸F-VS-labeled PSMA ligands are promising PET agents with prominent tumor uptake and high contrast. The lead agents ¹⁸F-PEG₂-VS-PSMAi and ¹⁸F-PEG₃-VS-PSMAi warrant further evaluation in prostate cancer patients.