tanaproget and Breast-Neoplasms

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

Topics: Benzoxazines; Breast Neoplasms; Carbon Radioisotopes; Humans; Parietal Lobe; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Progesterone; Thiones; Thiourea

The progesterone receptor (PR) is estrogen regulated, and PR levels in breast tumors can be used to predict the success of endocrine therapies targeting the estrogen receptor (ER). Tanaproget is a nonsteroidal progestin agonist with very high PR binding affinity and excellent in vivo potency. When appropriately radiolabeled, it might be used to image PR-positive breast tumors noninvasively by positron emission tomography (PET). We describe the synthesis and PR binding affinities of a series of fluoroalkyl-substituted 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones, analogues of Tanaproget. Some of these compounds have subnanomolar binding affinities, higher than that of either Tanaproget itself or the high affinity PR ligand R5020. Structure-binding affinity relationships can be rationalized by molecular modeling of ligand complexes with PR, and the enantioselectivity of binding has been predicted. These compounds are being further evaluated as potential diagnostic PET imaging agents for breast cancer, and enantiomerically pure materials of defined stereochemistry are being prepared.

Topics: Animals; Benzoxazines; Binding, Competitive; Breast Neoplasms; Female; Fluorine; Fluorine Radioisotopes; Models, Molecular; Promegestone; Radioligand Assay; Rats; Receptors, Progesterone; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; Thiones

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-[(18)F]Fluoropropyl-Tanaproget ([(18)F]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, [(18)F]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 [(18)F]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.

Topics: Animals; Benzoxazines; Binding Sites; Breast Neoplasms; Estrogens; Female; Fluorine Radioisotopes; Ovary; Positron-Emission Tomography; Rats; Receptors, Progesterone; Stimulation, Chemical; Thiones; Time Factors; Tissue Distribution; Uterus

Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC(50) value of 0.02 nm) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.

Topics: Alkaline Phosphatase; Amino Acid Substitution; Benzoxazines; Binding Sites; Breast Neoplasms; Cell Line, Tumor; Humans; Ligands; Mutagenesis, Site-Directed; Promegestone; Pyrroles; Receptors, Progesterone; Recombinant Proteins; X-Ray Diffraction