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

Abstract

Prostate-specific membrane antigen (PSMA) is a membrane protein highly expressed on prostate cancer cells and a potential imaging target for diagnosis. ¹⁸F-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 4-¹⁸F-fluorobenzoate (¹⁸F-SFB), a rapid and effective ¹⁸F-labeling agent, taking advantage of the high radiochemical yield of this compound. We evaluated the probes as PET probes for PSMA imaging. Four ¹⁸F-labeled probes, ¹⁸F-8a, ¹⁸F-8b, ¹⁸F-10a, and ¹⁸F-10b, were synthesized using ¹⁸F-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, ¹⁸F-8a and ¹⁸F-10a, and a toxicologic study of ¹⁸F-10a was performed. Four ¹⁸F-labeled asymmetric urea compounds, conjugated with ¹⁸F-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 ¹⁸F-DCFPyL, the probe currently used in clinical studies. All 4 compounds showed high affinity for PSMA. ¹⁸F-8a and ¹⁸F-10a had a particularly high binding affinity (Ki values of 3.35 and 2.23 nM, respectively). In the biodistribution study, the accumulation of ¹⁸F-8a (13.3 ± 2.2 percentage injected dose per gram [%ID/g]) and ¹⁸F-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 ¹⁸F-DCFPyL (16.0 ± 2.9 %ID/g). ¹⁸F-10a showed the lowest hepatic and intestinal accumulation among the 4 compounds and slightly slower blood clearance than others. In the PET imaging studies, ¹⁸F-8a and ¹⁸F-10a were clearly visualized in LNCaP in xenograft-bearing mice. ¹⁸F-10a showed higher LNCaP-to-liver ratios than ¹⁸F-8a. We confirmed the safety profiles of ¹⁸F-10a; the no-observed-adverse-effects level was larger than 13.2 μg/kg. A novel ¹⁸F-labeled asymmetric urea compound, ¹⁸F-10a, had a high radiochemical yield, high binding affinity for PSMA, and pharmacokinetic profiles suitable for a PSMA imaging probe. We believe that ¹⁸F-10a can be effectively and safely used in this type of imaging.