title: Synthesis and pre-clinical evaluation of a new class of high-affinity18F-labeled PSMA ligands for detection of prostate cancer by PET imaging.
abstract: OBJECTIVE
  Current clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features68Ga-labeled tracers, notably [68Ga]Ga-PSMA-HBED-CC. The longer half-life of fluorine-18 offers significant advantages over Ga-68, clinically and logistically. We aimed to develop high-affinity PSMA inhibitors labeled with fluorine-18 as alternative tracers for prostate cancer.
  
  
  METHODS
  Six triazolylphenyl ureas and their alkyne precursors were synthesized from the Glu-urea-Lys PSMA binding moiety. PSMA affinity was determined in a competitive binding assay using LNCaP cells. The [18F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [18F]fluoroethylazide. The18F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL. Biodistribution studies of the two tracers with the highest imaged-derived tumor uptake and highest PSMA affinity were undertaken at 1 h, 2 h and 4 h post-injection (p.i.), and co-administration of PMPA was used to determine whether uptake was PSMA-specific.
  
  
  RESULTS
  F-18-labeled triazolylphenyl ureas were prepared with a decay-corrected RCY of 20-40 %, >98 % radiochemical and chemical purity, and specific activity of up to 391 GBq/μmol. PSMA binding (IC50) ranged from 3-36 nM. The position of the triazole influenced tumor uptake (3 > 4 > 2), and direct conjugation of the triazole with the phenylurea moiety was preferred to insertion of a spacer group. Image-derived tumor uptake ranged from 6-14 %ID/g at 2 h p.i., the time of maximum tumor uptake; uptake of [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL was 5-6 %ID/g at 1-3 h p.i., the time of maximum tumor uptake. Biodistribution studies of the two most promising compounds gave maximum tumor uptakes of 10.9 ± 1.0 % and 14.3 ± 2.5 %ID/g, respectively, as compared to 6.27 ± 1.44 %ID/g for [68Ga]Ga-PSMA-HBED-CC.
  
  
  CONCLUSIONS
  Six [18F]triazolylphenyl ureas were prepared in good radiochemical yield. Compounds showed PSMA-specific uptake in LNCaP tumors as high as 14 % ID/g, more than a 2-fold increase over [68Ga]Ga-PSMA-HBED-CC. The facile and high-yielding radiosynthesis of these18F-labeled triazoles as well as their promising in vitro and in vivo characteristics make them worthy of clinical development for PET imaging of prostate cancer.
authors.affiliation: Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kelly
authors.affiliation: Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Amor-Coarasa
authors.affiliation: Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA.|Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, 10021, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nikolopoulou
authors.affiliation: Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, 10021, USA.
authors.forename: Dohyun
authors.initials: D
authors.lastname: Kim
authors.affiliation: Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA.
authors.forename: Clarence
authors.initials: C
authors.lastname: Williams
authors.affiliation: Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA.
authors.forename: Shashikanth
authors.initials: S
authors.lastname: Ponnala
authors.affiliation: Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA. job2060@med.cornell.edu.|Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, 10021, USA. job2060@med.cornell.edu.|Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10021, USA. job2060@med.cornell.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes / Q000737:chemistry; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D000954:Antigens, Surface; D005462:Fluorine Radioisotopes; D008024:Ligands; D010671:Phenylurea Compounds; D019275:Radiopharmaceuticals; D014230:Triazoles; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: Fluorine-18; PSMA; Prostate cancer; Triazolylphenyl ureas