Synthesis and Biological Evaluation of Novel 18F-Labeled Probes Targeting Prostate-Specific Membrane Antigen for Positron Emission Tomography of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a membrane protein highly expressed on prostate cancer cells and a potential imaging target for diagnosis. [(18)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-[(18)F]fluorobenzoate ([(18)F]SFB), a rapid and effective (18)F-labeling agent, taking advantage of the high radiochemical yield of this compound. We evaluated the probes as positron emission tomography (PET) probes for PSMA imaging.

Four (18)F-labeled probes [(18)F] 8A: , [(18)F] 8B: , [(18)F] 10A: , and [(18)F] 10B: , were synthesized using [(18)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 two compounds, [(18)F] 8A: and [(18)F] 10A: , and a toxicological study of [(18)F] 10A: was performed.

Four (18)F-labeled asymmetric urea compounds, conjugated with [(18)F]SFB, were synthesized at a radiochemical yield of 30%-50% (decay-corrected) with a radiochemical purity >95%. The radiochemical yield was 10-15 times higher than that of [(18)F]DCFPyL, the probe currently used in clinical studies. All four compounds showed high affinity for PSMA. [(18)F] 8A: and [(18)F] 10A: had a particularly high binding affinity (Ki values 3.35 nM and 2.23 nM, respectively). In the biodistribution study, the accumulation of [(18)F] 8A: (13.3 ± 2.2 %ID/g) and [(18)F] 10A: (14.0 ± 3.1 %ID/g) in PSMA-positive human prostate (LNCaP) tumors was higher than that of the other two compounds and similar to that of [(18)F]DCFPyL (16.0 ± 2.9 %ID/g). [(18)F] 10A: showed the lowest hepatic and intestinal accumulation among the four compounds and slightly slower blood clearance than others. In the PET imaging studies, [(18)F] 8A: and [(18)F] 10A: were clearly visualized in LNCaP in xenograft-bearing mice. [(18)F] 10A: showed higher LNCaP/liver ratios than [(18)F] 8A: We confirmed the safety profiles of [(18)F] 10A: ; the no observed adverse effects level was larger than 13.2 μg/kg.

A novel (18)F-labeled asymmetric urea compound [(18)F] 10A: had a high radiochemical yield, high binding affinity for PSMA, and pharmacokinetic profiles suitable for a PSMA imaging probe. We believe that [(18)F] 10A: can be effectively and safely used in this type of imaging.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2016 Jul 14 [Epub ahead of print]

Naoya Harada, Hiroyuki Kimura, Satoru Onoe, Hiroyuki Watanabe, Daiko Matsuoka, Kenji Arimitsu, Masahiro Ono, Hideo Saji

Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.