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Tremendous efforts are currently dedicated to the development of novel therapies targeting the androgen receptor (AR), the major driver of prostate cancer disease and its progression to castration resistance. The ability to noninvasively interrogate AR expression over time in murine models of prostate cancer would permit longitudinal preclinical analysis of novel compounds that could not otherwise be accomplished ex vivo. Although PET imaging with 16β- 18 F-fluoro-5α-dihydrotestosterone ( 18 F-FDHT) has successfully quantified AR levels clinically, no rodent model of 18 F-FDHT imaging has been reported so far. One difference between humans and rodents is the absence in the latter of the sex hormone-binding globulin (SHBG), a glycoprotein that binds to testosterone in the bloodstream, Here, we explore the role of SHBG in developing a working model of rodent AR imaging. Methods: Three human prostate cancer cell lines and xenografts (LNCaP, 22Rv1, and PC3) were used to examine the uptake of free 18 F-FDHT and SHBG-bound 18 F-FDHT. Both ligands were examined for stability and competitive binding to AR over time in vitro before in vivo studies. PET/CT imaging was used to dynamically measure the uptake of both tracers over 4 h, whereas specificity was determined by competitive binding with the AR antagonist enzalutamide. Results: AR levels correlated with the uptake of both 18 F-FDHT and SHBG- 18 F-FDHT in prostate cancer cell lines. Interestingly, whereas both free and SHBG-bound 18 F-FDHT had a similar cellular accumulation at 1 and 2.5 h, SHBG- 18 F-FDHT accumulated at significantly higher levels after 4 h-evidence that receptor-mediated uptake of SHBG accounted for later time-point differences. This observation was also seen in 22Rv1 tumor-bearing mice, in which SHBG- 18 F-FDHT exhibited a significantly increased uptake (average tumor-to-background ratio [TBR], 1.62 ± 0.62) in comparison to unbound 18 F-FDHT (TBR, 0.81 ± 0.08) at 4 h. Furthermore, the specificity of the SHBG- 18 F-FDHT accumulation at 4 h was demonstrated by a reduced tumor uptake after AR blockade with enzalutamide (TBR, 1.07 ± 0.13). Conclusion: Prebinding of 18 F-FDHT to SHBG allows accurate and quantitative PET imaging of AR levels in murine models of prostate cancer. This procedure may permit the use of PET imaging to study the longitudinal effects of AR-targeting therapies, accelerating novel-drug development.

the journal of nuclear medicine

Specific <sup>18</sup>F-FDHT Accumulation in Human Prostate Cancer Xenograft Murine Models Is Facilitated by Prebinding to Sex Hormone–Binding Globulin

Specific 18F-FDHT Accumulation in Human Prostate Cancer Xenograft Murine Models Is Facilitated by Prebinding to Sex Hormone–Binding Globulin

Specific ¹⁸F-FDHT Accumulation in Human Prostate Cancer Xenograft Murine Models Is Facilitated by Prebinding to Sex Hormone–Binding Globulin