18F-RB390: innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET)

Prostate. 2015 Mar 1;75(4):348-59. doi: 10.1002/pros.22919. Epub 2014 Oct 30.

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.

Conclusion: 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.

Keywords: 18F-DHT-derivative; PET-Imaging; PET/CT scan; T877A-androgen receptor mutant; androgen receptor; prostate cancer.

MeSH terms

  • Animals
  • Humans
  • Liver / diagnostic imaging
  • Liver / metabolism
  • Male
  • Mice
  • Positron-Emission Tomography / methods*
  • Prostatic Neoplasms / diagnostic imaging*
  • Prostatic Neoplasms / pathology
  • Radiopharmaceuticals*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*

Substances

  • Radiopharmaceuticals
  • Receptors, Androgen