Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsA 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.
Highlights
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
Chemistry A focused library of benzoxazin(thi)one compounds (Fig. 2) was synthesised using two routes: Route A (Scheme 1a), where benzoxazinone compounds were synthesised from aryl-bromide 1a using palladium catalysed Suzuki-coupling chemistry with commercially available fluorine-substituted boronic acids; compounds 1, 3 and 5 were accessed in ca 18% yield
Tanaproget was included as a positive control and the EC50 was comparable with the literature (T47D EC50 = 0.15 nM) (Fensome et al, 2005)
Summary
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. Targeting ER with selective estrogen receptor modulators (SERMs) is a successful therapy in breast cancer for patients who express functioning ER (Osborne, 1998). PET can be used as a predictive biomarker for patient stratification and/or a therapy response biomarker for monitoring treatment; in the case of breast cancer, both a predictive and therapy response marker are desirable (Banerji and Workman, 2016, Mankoff et al, 2008). Monitoring treatment response using [18F]FES, where the ligand binding domain (LBD) of ER is saturated by a therapeutic dose of endocrine therapy agent, requires sufficient time for drug washout for post-treatment scans. [18F]FES is ideally suited for measuring pre-treatment target expression and drug occupancy of the receptor (Mankoff et al, 2017)
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