Tanaproget

The progesterone receptor (PR) plays an important role in various physiological processes, especially in the female reproductive system, and abnormalities of PR function are associated with several diseases, including some types of cancer. Non-steroidal PR ligands are of interest as candidate drugs for treatment of PR-related diseases without the serious adverse effects that may be caused by steroidal ligands. For the development of non-steroidal PR ligands, both a hydrophobic backbone and a polar functional group corresponding to the 3-carbonyl group of progesterone, which interacts with Gln725 and Arg766 of the PR-ligand binding domain, are critically important. We previously showed that carborane is a useful hydrophobic pharmacophore for PR antagonists, and in this work, we introduced the pentafluorosulfanyl (SF₅) group as a novel polar functional group of carborane-based non-steroidal PR antagonists. All the synthesized SF₅-containing carborane derivatives exhibited PR-antagonistic activity at micromolar or submicromolar concentration. Among them, compounds 11 are potent progesterone antagonists with submicromolar IC₅₀ values.

The histological evaluation of estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer lesions from biopsy tissue can stratify patients to receive endocrine therapy. Furthermore, PR expression can predict response to selective estrogen receptor modulators (SERMs). Current immunohistochemical approaches to PR detection are limited by sampling error associated with biopsy and lack of standardised protocols; positron emission tomography (PET) using receptor targeted radiopharmaceuticals to provide quantitative, whole-body imaging may overcome these limitations. PR expression has been successfully imaged with PET in the clinical setting, however investigation into new radioligands with improved pharmacokinetics and metabolic stability is desirable.

We report the synthesis of a focused library of non-steroidal PR ligands evaluated for use as PET radioligands. A lead candidate ([¹⁸F]2) with low nanomolar activity was selected and radiolabelled with a radiochemical yield of 2.29 ± 2.31% (decay-corrected), radiochemical purity (RCP) > 95% and a molar activity of 2.5 ± 1.6 GBq/μmol. Cell uptake studies showed a significant and specific accumulation of [¹⁸F]2 in T47D (PR++) breast cancer cell compared to MDA-MB-231 (PR-) control; however, in vivo evaluation was confounded by rapid defluorination of the radioligand. In vitro metabolite analysis of 2 in MLM confirmed defluorination and oxidative metabolism of the thiocarbamate to oxocarbamate moiety by mass spectrometry.

A route to access [¹⁸F]2 was developed to allow in vitro and in vivo evaluation, albeit with low radiochemical yield and modest molar activity. [¹⁸F]2 demonstrated selective uptake in PR++ T47D cells which could be blocked in a dose dependent manner with progesterone. However, [¹⁸F]2 showed poor in vivo metabolic stability with rapid defluorination within the time frame of the imaging protocol.