title: 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 effective18F-labeling agent, taking advantage of the high radiochemical yield of this compound. We evaluated the probes as PET probes for PSMA imaging.
  
  
  METHODS
  Four18F-labeled probes,18F-8a,18F-8b,18F-10a, and18F-10b, were synthesized using18F-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 and18F-10a, and a toxicologic study of18F-10a was performed.
  
  
  RESULTS
  Four18F-labeled asymmetric urea compounds, conjugated with18F-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 of18F-DCFPyL, the probe currently used in clinical studies. All 4 compounds showed high affinity for PSMA.18F-8a and18F-10a had a particularly high binding affinity (Ki values of 3.35 and 2.23 nM, respectively). In the biodistribution study, the accumulation of18F-8a (13.3 ± 2.2 percentage injected dose per gram [%ID/g]) and18F-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 of18F-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 and18F-10a were clearly visualized in LNCaP in xenograft-bearing mice.18F-10a showed higher LNCaP-to-liver ratios than18F-8a. We confirmed the safety profiles of18F-10a; the no-observed-adverse-effects level was larger than 13.2 μg/kg.
  
  
  CONCLUSIONS
  A novel18F-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 that18F-10a can be effectively and safely used in this type of imaging.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Harada
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan.|Radioisotope Research Center of Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, Japan.|Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchicho, Misasagi, Yamashinaku, Kyoto, Japan; and.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Onoe
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan.
authors.forename: Daiko
authors.initials: D
authors.lastname: Matsuoka
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan.|School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyubancho, Nishinomiya, Hyogo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arimitsu
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto, Japan hsaji@pharm.kyoto-u.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D060326:Chemistry Techniques, Synthetic; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011854:Radiochemistry; D014018:Tissue Distribution
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D000954:Antigens, Surface; D001565:Benzoates; D015335:Molecular Probes; D009943:Organophosphorus Compounds; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; C022893:4-fluorobenzoic acid
keywords: 18F-SFB; 18F-labeled asymmetric urea compound; PET; PSMA; prostate cancer