The steroid hormones 17-β estradiol (E2) and progesterone (P4) can regulate capacitation, hyperactive motility, and the acrosome reaction (AR) during the sperm transit through the female tract. Moreover, exogenous P4 and E2 can induce the AR in ovine spermatozoa, and progesterone receptor (PR) and estrogen receptors (ERα and ERβ) are present in these cells. Thus, to investigate whether the effects both steroid hormones in ram sperm capacitation and AR are receptor-mediated, we incubated them with receptor agonists (tanaproget 1 μM and 5 μM for PR or resveratrol 5 μM and 10 μM for ER) or antagonists (mifepristone 4 μM and 40 μM for PR or tamoxifen 5 μM and 10 μM for ER) in capacitating conditions. The addition of receptor modulators did not affect sperm viability or total motility, although changes in progressive motility were detected. The incubation with both receptor agonists increased the percentage of acrosome-reacted spermatozoa, evaluated by chlortetracycline staining, when compared with the capacitated nontreated sample (Cap-C, P < 0.001). Moreover, the ER agonist resveratrol 10 μM provoked a greater AR than E2 (P < 0.01). Furthermore, the incubation with the receptor antagonists prevented the induction of the AR by P4 or E2, as the antagonists-treated spermatozoa presented a similar CTC pattern to that of Cap-C. In conclusion, these results confirm that P4 and E2 can induce the AR in ram spermatozoa and that this effect is receptor-mediated.

01 Dec 2019·EJNMMI Radiopharmacy and Chemistry

Synthesis of a benzoxazinthione derivative of tanaproget and pharmacological evaluation for PET imaging of PR expression

Article

Author: Miranda, Cecilia ; Cawthorne, Christopher ; Hayes, Angela ; Smith, Graham ; Raynaud, Florence ; Allott, Louis

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.

15 Jun 2015·Chemistry – A European JournalQ2 · CHEMISTRY

Carbon‐11 Radiolabelling of Organosulfur Compounds: ¹¹C Synthesis of the Progesterone Receptor Agonist Tanaproget

Q2 · CHEMISTRY

Article

Author: Haywood, Tom ; Kealey, Steven ; Plisson, Christophe ; Allott, Louis ; Sánchez-Cabezas, Santiago ; Miller, Philip W ; Hall, James J ; Smith, Graham

AbstractHerein a new 11C radiolabelling strategy for the fast and efficient synthesis of thioureas and related derivatives using the novel synthon, 11CS2, is reported. This approach has enabled the facile labelling of a potent progesterone receptor (PR) agonist, [11C]Tanaproget, by the intramolecular reaction of the acyclic aminohydroxyl precursor with 11CS2, which has potential applications as a positron emission tomography radioligand for cancer imaging.

100 Deals associated with Tanaproget

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KEGG	Wiki	ATC	Drug Bank
D06003	Tanaproget	-	DB04787

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Indication	Highest Phase	Country/Location	Organization	Date
Contraception	Phase 2	-	Pfizer Inc.	-
Contraception	Phase 2	-	Ligand Pharmaceuticals, Inc.	-
Menopausal syndrome	Phase 2	US	-	-
Pregnancy	Phase 2	US	-	-

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