title: 18F-RB390: innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET).
abstract: BACKGROUND
  Detecting prostate cancer before spreading or predicting a favorable therapy are challenging issues for impacting patient's survival. Presently, 2-[(18) F]-fluoro-2-deoxy-D-glucose ((18) F-FDG) and/or (18) F-fluorocholine ((18) F-FCH) are the generally used PET-tracers in oncology yet do not emphasize the T877A androgen receptor (AR) mutation being exclusively present in cancerous tissue and escaping androgen deprivation treatment.
  
  
  METHODS
  We designed and synthesized fluorinated 5α-dihydrotestosterone (DHT) derivatives to target T877A-AR. We performed binding assays to select suitable candidates using COS-7 cells transfected with wild-type or T877A AR (WT-AR, T877A-AR) expressing plasmids and investigated cellular uptake of candidate (18) F-RB390. Stability, biodistribution analyses and PET-Imaging were assessed by injecting (18) F-RB390 (10MBq), with and without co-injection of an excess of unlabeled DHT in C4-2 and PC-3 tumor bearing male SCID mice (n = 12).
  
  
  RESULTS
  RB390 presented a higher relative binding affinity (RBA) (28.1%, IC50  = 32 nM) for T877A-AR than for WT-AR (1.7%, IC50  = 357 nM) related to DHT (RBA = 100%). A small fraction of (18) F-RB390 was metabolized when incubated with murine liver homogenate or human blood for 3 hr. The metabolite of RB390, 3-hydroxysteroid RB448, presented similar binding characteristics as RB390. (18) F-RB390 but not (18) F-FDG or (18) F-FCH accumulated 2.5× more in COS-7 cells transfected with pSG5AR-T877A than with control plasmid. Accumulation was reduced with an excess of DHT. PET/CT imaging and biodistribution studies revealed a significantly higher uptake of (18) F-RB390 in T877A mutation positive xenografts compared to PC-3 control tumors. This effect was blunted with DHT.
  
  
  CONCLUSIONS
  Given the differential binding capacity and the favorable radioactivity pattern, (18) F-RB390 represents the portrayal of the first imaging ligand with predictive potential for mutant T877A-AR in prostate cancer for guiding therapy. Prostate 75:348-359, 2015. © 2014 Wiley Periodicals, Inc.
authors.affiliation: Department of Nephrology & Hypertension and Clinical Pharmacology, University of Berne, Berne, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Bertolini
authors.forename: Christine
authors.initials: C
authors.lastname: Goepfert
authors.forename: Thomas
authors.initials: T
authors.lastname: Andrieu
authors.forename: Sara
authors.initials: S
authors.lastname: Nichols
authors.forename: Martin A
authors.initials: MA
authors.lastname: Walter
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Frey
mesh_terms: D000818:Animals; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
chemical_list: D019275:Radiopharmaceuticals; D011944:Receptors, Androgen
keywords: 18F-DHT-derivative; PET-Imaging; PET/CT scan; T877A-androgen receptor mutant; androgen receptor; prostate cancer