Effect of Androgen on [¹⁸F]-29-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (¹⁸F-FMAU) Biodistribution

Objectives: Imaging assessment of cellular proliferation may allow prediction of the transition from castrate-sensitive to castrate-resistant clinical state. We therefore assessed the association between the presence and absence of androgen on the physiologic biodistribution of the positron emission tomography cellular imaging biomarker, [¹⁸F]-29-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (¹⁸F-FMAU).

Methods: Noncastrated (n=4) and castrated (n=4) athymic non-tumor bearing male mice served as models for presence and absence, respectively, of androgens. MicroPET scans were performed immediately following tail vein administration of 200 uCi of ¹⁸F-FMAU and dynamic PET scanning for 1 hour followed by microCT imaging for anatomic reference. PET and CT images were coregistered using rigid transformations. CT-based regions of interest were drawn over 3 selected organs (liver, heart, muscle) to obtain mean standardized uptake value (SUVmean). Imaging was performed at baseline on 4 noncastrated and 4 castrated mice. The 4 castrated animals were then imaged longitudinally on days 7, 15, 21, 28 and 35 following s.c. introduction of a 21-day release dihydrotestosterone (DHT) pellet on day 0. Several two-group comparisons of average of SUVmean of 3 organs across the imaging days and two animal castration states were performed.

Results: Table 1 summarizes the organ SUVmean at 1 h. The mean SUVs (+/-s.d.) for 3 organs were significantly different between noncastrated and pre-pellet castrated mice at baseline (liver: 1.12+/-0.04 vs 0.83+/-0.07; heart: 0.95+/-0.04 vs 0.67+/-0.10; muscle: 1.02+/-0.06 vs 0.63+/-0.04, respectively, p<0.05). This difference remained in effect for all organs on day 7 and for heart and muscle on day 15. Average organ SUVmean increased on day 15 and reached peak values on day 28 (liver: 1.55+/-0.17; heart: 1.21+/-0.14; muscle: 1.30+/-0.18) and were significantly higher from corresponding baseline levels in both noncastrate and castrate animals. The peak values decreased significantly by day 35 (14 days after end of pellet DHT release) and were not significantly different from baseline values.

Conclusion: There is a significant association between androgen presence or absence on normal biodistribution of the ¹⁸F-FMAU in mice liver, heart and muscle tissues. The modulatory effect may be due to androgen control of mitochondrial function including thymidine kinase 2 activity. Our investigation suggests that assessment of ¹⁸F-FMAU PET studies in prostate cancer may need to take into account the effect of androgen-based treatments and may also be useful in prediction of transit from castration-sensitive to castration-resistant state. Research Support: Supported by the National Institutes of Health grants R21-CA142426 (PI: H. Jadvar), R21-EB017568 (PI: H. Jadvar), P30-CA01408 (USC Norris Comprehensive Cancer Center) and the Whittier Foundation (PI: H. Jadvar). The radiochemistry preparation and procedures for ¹⁸F-FMAU have been patented under US patent 7,273,600 B2 (inventors: P.S. Conti, M.M. Alauddin, J.D. Fissekis), and the patent has been assigned to the University of Southern California, Los Angeles, CA. None of the authors have any financial interest in this patent. FDA IND 129512.