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Fluorine-Substituted Tanaproget As a Progesterone Receptor Imaging Agent for Positron Emission Tomography

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Fluorine-Substituted Tanaproget As a Progesterone Receptor Imaging Agent for Positron Emission Tomography 中国科技论文在线 http://www.paper.edu.cn 1096 Bioconjugate Chem. 2010, 21, 1096–1104 Development of [F-18]Fluorine-Substituted Tanaproget as a Progesterone Receptor Imaging Agent for Positron Emission Tomography Jae Hak Lee,‡ Hai-bing Zhou,†,‡ Carmen S. Dence,§ Kathryn E. Carlson,‡ Michael J. Welch,§ and John A. Katzenellenbogen*,‡ Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Matthews Avenue, Urbana, Illinois 61801, and Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway, St. Louis, Missouri 63110. Received February 24, 2010; Revised Manuscript Received March 29, 2010 The level of progesterone receptors (PRs) in breast tumors can be used to guide the selection of endocrine therapies for breast cancer patients. To this end, we have prepared a fluorine-18 labeled analogue of Tanaproget, a nonsteroidal progestin with very high PR binding affinity and low affinity for androgen and glucocorticoid receptors, and have studied its tissue distribution in estrogen-primed rats to evaluate its potential for imaging PR levels by positron emission tomography. 4-[18F]Fluoropropyl-Tanaproget ([18F]9, FPTP) was prepared in three steps, within 140 min at an overall decay-corrected yield of 5% and effective specific activity of >550 Ci/mmol. In biodistribution studies, [18F]9 uptake was high in target tissues at both 1 and 3 h (uterus, 4.55 and 5.26%ID/g; ovary, 2.32 and 2.20%ID/g, respectively) and was cleanly blocked by coinjection of excess unlabeled compound. Uterus to blood and muscle activity ratios were 9.2 and 5.2 at 1 h and 32 and 26 at 3 h, respectively. The biodistribution of [18F]9 compares favorably to that of previously prepared F-18 labeled steroidal progestins, FENP and FFNP. Its high target tissue uptake efficiency and selectivity, and prolonged retention, suggest that it has excellent promise as a PET imaging agent for PR-positive breast tumors. INTRODUCTION limited progress has been made with PET imaging of PR (19-22). Receptor-targeted radiopharmaceuticals are designed to image specific molecular targets and thereby obtain quantitative Because PR levels are regulated through ER, breast tumor information about important metabolic, physiological, and PR levels have been used, together with ER levels, to predict pathological processes in living systems. Steroid receptors, patient response to ER-targeted therapies (either antiestrogens members of the nuclear hormone receptor superfamily, are key or aromatase inhibitors) (2). In fact, because PR levels are regulators of gene expression and cellular function, and have increased by estrogen treatment, measurement of an increase emerged as very attractive targets for imaging (1). The activity in PR levels in breast tumors by PET, after a brief exposure to of certain steroid receptors drives the growth of hormone- estrogen, might be useful in assessing whether the ER is responsive cancers, both the estrogen receptor (ER) and the functional and thus capable of mediating endocrine therapies progesterone receptor (PR) in breast cancer, and the androgen (19, 23). PR itself is also a target for endocrine therapy in breast receptor (AR) in prostate cancer. Consequently, these receptors cancer using antiprogestins (24). are both biomarkers for diagnosis and targets for cancer Currently, most PR ligands are steroidal compounds having endocrine therapies (1). similar core structures (Figure 1) (25, 26). In the search for Currently, measurements of tumor ER, PR, or AR levels are diagnostic PR tumor imaging agents, some of these have been 2-4 labeled with radionuclides such as F-18, I-123, and Br-76 done in vitro by immunohistochemical assays ( ), but there - ) + is great interest in developing methods to determine receptor (1, 21, 27 29). Because fluorine-18 (t1/2 110 min, levels by in vivo imaging using positron emission tomography emitting) has the most favorable nuclear and physical properties for PET imaging, we and others have investigated the in vivo (PET), which could potentially measure receptor levels at all 18 tumor sites, simultaneously and noninvasively (1, 5-8). This behavior of two F-18 labeled steroidal progestins, 21-[ F]fluoro- 16R-ethyl-norprogesterone ([18F]FENP, 2) and 21-[18F]fluoro- information could be used to select patients most likely to benefit 18 from endocrine therapies, thereby sparing some the morbidity furanyl-norprogesterone ([ F]FFNP, 5). FENP, based on the of radiation and chemotherapy. Clinical PET imaging of ER in well-known, potent Organon progestin, ORG2058 (1), has very breast cancer using 16R-[18F]fluoroestradiol (FES) (9-14) and high binding affinity and showed excellent target tissue uptake AR in prostate cancer using 16-[18F]fluoro-5R-dihydrotest- efficiency and selectivity in estrogen-primed rats, but surpris- osterone (FDHT) (15-18) is quite advanced, but thus far, only ingly failed to image PR in humans (20). This species difference was traced to 20-hydroxysteroid dehydrogenase (20-HSD) activity, present in the blood of humans but not rodents, that * To whom correspondence should be addressed: Prof. John A. rapidly converts FENP into the inactive 20-hydroxy analogue Katzenellenbogen, Department of Chemistry, University of Illinois at (27). FFNP (19), on the other hand, appears resistant to this Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL, 61801. + + dehydrogenase and is currently being evaluated as a PET PR Telephone: 1-217-333-6310, Fax: 1-217-333-7325, E-mail: jkatzene@ imaging agent in humans. uiuc.edu. † Current address: College of Pharmacy, Wuhan University, Wuhan, Despite the continuing promise of FFNP, there are potential 430072 China. liabilities in using 20-keto steroids as PR PET imaging agents, ‡ University of Illinois at Urbana-Champaign. because steroidal progestins often show cross reactivity with § Washington University School of Medicine. other steroid receptors, notably the glucocorticoid receptor (GR) 10.1021/bc1001054 2010 American Chemical Society Published on Web 05/24/2010 转载 中国科技论文在线 http://www.paper.edu.cn 18Fl-Substituted Tanaproget as a PR Imaging Agent Bioconjugate Chem., Vol. 21, No. 6, 2010 1097 Figure 1. Structure and PR binding affinity of some steroidal (1-5) and nonsteroidal (6-9) progestins in the series leading to the F-18 labeled analogues, FENP (2), FFNP (5), and FPTP (9). and AR (30), and the inactivating metabolism by the 20-HSD Our original route to unlabeled FTPT was not well suited is still possible (27). Additionally, steroids generally have high for F-18 labeling, because fluoride ion was introduced early in lipophilicity, which could increase nonspecific binding. the sequence, and three subsequent steps were required to A number of pharmaceutical companies have reported non- produce the final product. In our first approach to develop an steroidal progestins with high PR binding affinity and excellent alternative synthesis more amenable to F-18 labeling, we tried selectivity (26, 31-33). We were particularly attracted to to prepare a precursor in which F-18 could be introduced in Tanaproget (7), a nonsteroidal progestin developed by Wyeth, the last step by fluoride ion displacement of a methanesulfonate that is based on a dihydrobenzoxazinethione core structure. Its analogue of FTPT itself (or a BOC-protected version). How- PR binding affinity is very high, nearly twice that of the potent ever, the alcohol in the hydroxypropyl group was not stable steroidal progestin R5020, giving it an estimated KD of ∼0.2 under the harsh conditions required to convert the carbamate nM (34, 35); its affinity for GR and AR is also very low. Thus, to the thiocarbamate with Lawesson’s reagent. It was also very if the F-18 radionuclide could be introduced into Tanaproget unlikely that the electrophilic methanesulfonate group would or a high-affinity analogue, it might be an effective PET imaging have been compatible with the nucleophilic thiocarbamate agent for PR-positive tumors. function under the conditions required for fluoride ion substitu- We recently reported the syntheses and binding affinity of tion. We therefore turned to the use of the methanesulfonate of several Tanaproget derivatives containing fluoroethyl or fluo- the corresponding carbamate (12), thinking that the oxygen ropropyl substituents as potential PET PR imaging agents, would be less nucleophilic than the sulfur. As shown in Scheme including ones having affinities higher than Tanaproget itself 1, synthesis of this precursor began with allylcarbmate 10, which (36). In this report, we describe synthesis of [18F]fluoropropyl- was hydroborated and oxidized to give corresponding hydroxyl Tanaproget (FPTP, 9), and we evaluate its tissue distribution compound 11 in good yield (74%). Subsequent treatment with in estrogen-primed immature female rats. Its target tissue uptake methansulfonyl chloride and triethylamine furnished the desired efficiency, selectivity, and specificity are excellent, and compare labeling precursor 12 in good yield (79%). favorably with those of FENP and FFNP. Therefore, it appears In model reactions for F-18 labeling, and to prepare authentic to be an excellent prospect for further evaluation as an agent samples of the unlabeled compounds, mesylate 12 was treated for PET imaging of PR in breast tumors. with tetrabutylammonium fluoride (TBAF) in tert-butyl alcohol at 90 °C for 2 h, followed after solvent removal by heating at RESULTS 160 °C neat for 20 min to remove the BOC protecting group Chemistry. Synthesis of Fluoropropyl Tanaproget Deri- on the pyrrole. This one-pot/two-step sequence provided the VatiVes. Guided by the structure-affinity relationships in the fluorinated carbamate 13 in a high yield (81%). As has been Tanaproget series, available in the literature, we synthesized a observed in other systems (37-41), use of this protic solvent number of Tanaproget analogues containing 2-fluoroethyl and protocol for the fluoride substitution step was effective in 3-fluoropropyl groups. These are described in our recent reducing the formation of side products through elimination or publication (36). Substitution on the pyrrole nitrogen gave lower- hydrolysis, and gave high yields of the fluorinated product.
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