18F‐RB390: Innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET). Issue 4 (30th October 2014)

• Record Type: Journal Article
• Authors: Bertolini, Reto; Goepfert, Christine; Andrieu, Thomas; Nichols, Sara; Walter, Martin A.; Frey, Felix J.; McCammon, J. Andrew; Frey, Brigitte M.
• Is Part Of: Prostate. Volume 75:Issue 4(2015)
• Page Start: 348
• Page End: 359
• Publication Date: 2014-10-30
• Subjects: Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.22919
• Languages: English
• ISSNs: 0270-4137

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="pros22919-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>Detecting prostate cancer before spreading or predicting a favorable therapy are challenging issues for impacting patient's survival. Presently, 2‐[<sup>18</sup>F]‐fluoro‐2‐deoxy‐<sc>D</sc>‐glucose (<sup>18</sup>F‐FDG) and/or <sup>18</sup>F‐fluorocholine (<sup>18</sup>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.</p> </sec> <sec id="pros22919-sec-0002" sec-type="section"> <title>METHODS</title> <p>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 <sup><bold>18</bold></sup><bold>F‐RB390</bold>. Stability, biodistribution analyses and PET‐Imaging were assessed by injecting <sup>18</sup>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).</p> </sec> <sec id="pros22919-sec-0003" sec-type="section"> <title>RESULTS</title> <p> <bold>RB390</bold> presented a higher relative binding affinity (RBA) (28.1%, IC<sub>50</sub> = 32 nM) for T877A‐AR than for WT‐AR (1.7%, IC<sub>50</sub> = 357 nM) related to DHT (RBA = 100%). A small fraction of <sup><bold>18</bold></sup><bold>F‐RB390</bold> was metabolized when incubated with murine liver homogenate or human blood for 3 hr. The metabolite of <bold>RB390</bold>, 3‐hydroxysteroid <bold>RB448</bold>, presented similar binding characteristics as <bold>RB390</bold>. <sup><bold>18</bold></sup><bold>F‐RB390</bold> but not <sup>18</sup>F‐FDG or <sup>18</sup>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 <sup><bold>18</bold></sup><bold>F‐RB390</bold> in T877A mutation positive xenografts compared to PC‐3 control tumors. This effect was blunted with DHT.</p> </sec> <sec id="pros22919-sec-0004" sec-type="section"> <title>CONCLUSION</title> <p>Given the differential binding capacity and the favorable radioactivity pattern, <sup><bold>18</bold></sup><bold>F‐RB390</bold> represents the portrayal of the first imaging ligand with predictive potential for mutant T877A‐AR in prostate cancer for guiding therapy. <italic>Prostate 75:348–359, 2015</italic>. © 2014 Wiley Periodicals, Inc.</p> </sec> </abstract>