title: Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand.
abstract: OBJECTIVE
  The aim of this study was to synthesize and preclinically evaluate an18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.
  
  
  METHODS
  Several conditions for the labeling of18F-PSMA-11 via18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.
  
  
  RESULTS
  Quantitative labeling yields could be achieved with >97 % radiochemical purity. The18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv.
  
  
  CONCLUSIONS
  18F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible.
authors.affiliation: Department of Nuclear Medicine, S.Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Boschi
authors.affiliation: Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Seval
authors.initials: S
authors.lastname: Beykan
authors.affiliation: Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave. CHS AR-255, Los Angeles, CA, 90095, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Slavik
authors.affiliation: Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave. CHS AR-255, Los Angeles, CA, 90095, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Wei
authors.affiliation: Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave. CHS AR-255, Los Angeles, CA, 90095, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Spick
authors.affiliation: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Eberlein
authors.affiliation: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Buck
authors.affiliation: Department of Nuclear Medicine, S.Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Lodi
authors.affiliation: Department of Medical Physics, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Cicoria
authors.affiliation: Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave. CHS AR-255, Los Angeles, CA, 90095, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Czernin
authors.affiliation: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lassmann
authors.affiliation: Department of Nuclear Medicine, S.Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fanti
authors.affiliation: Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany. KHerrmann@mednet.ucla.edu.|Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave. CHS AR-255, Los Angeles, CA, 90095, USA. KHerrmann@mednet.ucla.edu.
authors.forename: Ken
authors.initials: K
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004492:Edetic Acid / Q000031:analogs & derivatives; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011829:Radiation Dosage; D000069079:Radiation Exposure / Q000032:analysis*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014915:Whole-Body Counting
chemical_list: D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D005462:Fluorine Radioisotopes; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D009842:Oligopeptides; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C000718244:gallium 68 PSMA-11; D004492:Edetic Acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: 18F; Dosimetry; PET; PSMA; Preclinical; Prostate cancer