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  • br Biodistribution studies br Biodistribution results of F F

    2019-09-16


    3.6. Biodistribution studies
    Biodistribution results of [18F]FPTT were shown in Fig. 5. At 1 h p.i., the uptakes in uterus and ovary of female SD rats that had been estrogen
    Fig. 3. Representative PET images of [18F]FPTT in PR-positive MCF-7 (A) and PR-negative MDA-MB-231 (B) tumors in tumor-bearing mice were obtained at 0.5, 1 and 2 h p.i. Quantitative tumor uptakes (C) and tumor-to-muscle ratios (D) derived from A and B. (n = 3, red dotted lines denote tumors, ***P b 0.001). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
    Fig. 4. (A) Representative PET images obtained at 1 h p.i. of [18F]FPTT in PR-positive MCF-7 tumor-bearing mice, and with excessive of ethisterone or nonradioactive Calcipotriol [19F]FPTT for blocking. Quantitative tumor uptakes (B) and tumor-to-muscle ratios (C) derived from A. (n = 3, red dotted lines denote tumors, ***P b 0.001). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
    Fig. 5. (A) Biodistribution of [18F]FPTT in estrogen-primed immature female SD rats at different time points, and in normal immature female SD rats with or without ethisterone blocking at 1 h p.i. The ratios of uterus-to-muscle (B) and ovary-to-muscle (C) of [18F]FPTT derived from A. (n = 4, ***P b 0.001; Expressed as mean ± standard deviation).
    pretreated to induce PR expression were 8.31 ± 1.74%ID/g and 3.79 ± 0.82%ID/g, respectively. While the uptakes in uterus and ovary of nor-mal rats (3.52 ± 0.29%ID/g and 3.22 ± 0.50%ID/g) were lower than that of estrogen-primed immature female SD rats (P b 0.05), and could be inhibited significantly by ethisterone (2.11 ± 0.18%ID/g and 1.77 ± 0.41%ID/g), indicating the specific uptakes of [18F]FPTT in PR-rich uterus and ovary. [18F]FPTT had low uptakes in the heart, spleen, lung and other non-target tissues and organs, which can be a benefit to improve imaging contrast. In addition, [18F]FPTT showed relatively low bone accumulation at different time points, revealing no defluorination occurred in vivo.
    4. Discussion
    Breast cancer PR expression is regulated by estrogen receptor (ER) and could be used for tumor diagnosis and to guide the antiestrogen treatment in breast cancer [29]. During the past a few decades, a variety of PR targeting radiotracers have been reported although the clinical translational study progress is limited when compared with ER imaging. 18F-labeled steroidal progestins of [18F]FENP and [18F]FMNP were re-ported by Martin et al. [15] and Verhagen et al. [14], respectively. Both radiotracers had specific uptakes in the uterus and ovaries of estrogen-induced SD rats, while the first one was found had no corre-lated with PR levels in human breast cancer and had high accumulation in bone [30]. Recently, the first-in-human study of [18F]FFNP was re-ported by Dehdashti et al. [16], which is the most successful PR targeting PET tracer so far [29]. In 2010, a nonsteroidal PR targeting probe [18F] FPTP was reported by Lee et al. [17], it had high target tissue specific up-take with prolonged retention. However, as a chiral compound, the bio-logical effects of its enantiomers remain to be studied.
    In recent years, our research group had focused on the development of radiotracers for breast cancer imaging [18,19,25,26,31], including two radiolabeled ethisterone derivatives [18F]EAEF [19] and [131I]EIPBA [18] for PR targeting. Although both of them exhibited high receptor binding affinity and PR-positive tumor uptake, however, the unfavorable liver uptake limits their potential application. In this study, a small PEG was coupled to ethinyl group of ethisterone to reduce the lipophilicity of tracer and expected to lower the liver uptake. After radiolabeled with 18F by one-step nucleophilic substitution reaction, the [18F]FPTT was prepared in high radiochemical yield with good radiochemical purity. Its octanol-to-water partition coefficient (log P) was determined as 0.22 ± 0.01, which much lower than that of [18F]EAEF (0.53 ± 0.06) and [131I]EIPBA (1.38 ± 0.48), indicating moderate lipophilicity. The nanomolar binding affinity of [18F]FPTT to PR (Kd = 29.54 ± 5.27 nM) was determined by cell binding assay. Of course, compared with re-ported [18F]FMNP, [18F]FENP and [18F]FFNP, the Kd of [18F]FPTT showed relatively moderate affinity, but slightly better hydrophilicity. A more systematic, detailed and multifaceted comparison with the reported classical probes will be studied in our next study.