@article {Harada1978, author = {Naoya Harada and Hiroyuki Kimura and Satoru Onoe and Hiroyuki Watanabe and Daiko Matsuoka and Kenji Arimitsu and Masahiro Ono and Hideo Saji}, title = {Synthesis and Biologic Evaluation of Novel 18F-Labeled Probes Targeting Prostate-Specific Membrane Antigen for PET of Prostate Cancer}, volume = {57}, number = {12}, pages = {1978--1984}, year = {2016}, doi = {10.2967/jnumed.116.175810}, publisher = {Society of Nuclear Medicine}, 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. Methods: 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{\textendash}bearing mice. PET images were obtained using 2 compounds, 18F-8a and 18F-10a, and a toxicologic study of 18F-10a was performed. Results: Four 18F-labeled asymmetric urea compounds, conjugated with 18F-SFB, were synthesized at a radiochemical yield of 30\%{\textendash}50\% (decay-corrected), with a radiochemical purity greater than 95\%. The radiochemical yield was 10{\textendash}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 {\textpm} 2.2 percentage injected dose per gram [\%ID/g]) and 18F-10a (14.0 {\textpm} 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 {\textpm} 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. Conclusion: 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.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/57/12/1978}, eprint = {https://jnm.snmjournals.org/content/57/12/1978.full.pdf}, journal = {Journal of Nuclear Medicine} }