Synthesis and Biologic Evaluation of Novel 18F-Labeled Probes Targeting Prostate-Specific Membrane Antigen for PET of Prostate Cancer.

Unlabelled: Prostate-specific membrane antigen (PSMA) is a membrane protein highly expressed on prostate cancer cells and a potential imaging target for diagnosis. F-DCFPyL has been recently developed as an effective probe with high diagnostic accuracy for prostate cancer imaging. However, its radiochemical yield is low. We developed new PSMA probes using succinimidyl 4-F-fluorobenzoate (F-SFB), a rapid and effective F-labeling agent, taking advantage of the high radiochemical yield of this compound. We evaluated the probes as PET probes for PSMA imaging.

Methods: Four F-labeled probes, F-8a, F-8b, F-10a, and F-10b, were synthesized using F-SFB, and their affinity for PSMA and partition coefficients (log D) were evaluated in vitro. Biodistribution studies were performed in human prostate cancer xenograft-bearing mice. PET images were obtained using 2 compounds, F-8a and F-10a, and a toxicologic study of F-10a was performed.

Results: Four F-labeled asymmetric urea compounds, conjugated with F-SFB, were synthesized at a radiochemical yield of 30%-50% (decay-corrected), with a radiochemical purity greater than 95%. The radiochemical yield was 10-15 times higher than that of F-DCFPyL, the probe currently used in clinical studies. All 4 compounds showed high affinity for PSMA. F-8a and F-10a had a particularly high binding affinity (Ki values of 3.35 and 2.23 nM, respectively). In the biodistribution study, the accumulation of F-8a (13.3 ± 2.2 percentage injected dose per gram [%ID/g]) and F-10a (14.0 ± 3.1 %ID/g) in PSMA-positive human prostate (LNCaP) tumors was higher than that of the other 2 compounds and similar to that of F-DCFPyL (16.0 ± 2.9 %ID/g). F-10a showed the lowest hepatic and intestinal accumulation among the 4 compounds and slightly slower blood clearance than others. In the PET imaging studies, F-8a and F-10a were clearly visualized in LNCaP in xenograft-bearing mice. F-10a showed higher LNCaP-to-liver ratios than F-8a. We confirmed the safety profiles of F-10a; the no-observed-adverse-effects level was larger than 13.2 μg/kg.

Conclusion: A novel F-labeled asymmetric urea compound, F-10a, had a high radiochemical yield, high binding affinity for PSMA, and pharmacokinetic profiles suitable for a PSMA imaging probe. We believe that F-10a can be effectively and safely used in this type of imaging.