Synthesis and biological evaluation of a nonsteroidal bromine-76-labeled androgen receptor ligand 3-[76Br]bromo-hydroxyflutamide

Parent, Ephraim E.; Jenks, Carl; Sharp, Terry L.; Welch, Michael J.; Katzenellenbogen, John A.

doi:10.1016/j.nucmedbio.2006.05.009

Cited by 30 publications

(14 citation statements)

References 39 publications

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“…Recent studies with nonsteroidal AR ligands indicate that differential tissue distribution by itself is not likely to explain differences in pharmacological responses seen in prostate and muscle (27). In addition, although AR binding involves ligand-induced conformational changes mediated via the ligand-binding domain, crystal structures of aryl propionamide and hydantoin SARMs do not show the same magnitude of conformational changes as seen with the SERM-bound ER ligand binding domain (28,29), particularly in the AF2 region (30,31).…”

Section: Selective Androgen Receptor Modulatorsmentioning

confidence: 99%

New selective estrogen and androgen receptor modulators

Clarke

Khosla

2009

Current Opinion in Rheumatology

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Purpose of Review The present review focuses on the most significant recent findings regarding selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs). SERMs, which interact with estrogen receptor (ER)-α and ER-β in multiple tissues, continue to generate clinical interest in potential applications in as many disorders as the tissues in which the two known receptors are found. SARMs have been demonstrated to have fewer clinical applications to date, but continue to be investigated for use in multiple disorders in which androgen receptor (AR) modulation is likely to be important. Both types of compounds hold great promise for therapeutic use in multiple hormonal disorders involving tissue-specific effects mediated by estrogen or androgen receptors. Recent Findings While SERMs have been available for clinical use for 50 years, recent investigation has focused on large randomized clinical trials for newer indications of older agents, or smaller clinical trials of newer agents with improved clinical activity and reduced side effects in specific tissues. In particular, the large, prospective, randomized, controlled, multi-year STAR and RUTH clinical trials have recently shown interesting similarities and differences between tamoxifen and raloxifene in estrogen-responsive tissues. Lasofoxifene and arzoxifene are two newer SERMs that have recently been demonstrated to improve bone mineral density and lower serum cholesterol values compared to older SERMs in smaller clinical trials. SARMs are a newer category of drug still being investigated mostly at the basic and preclinical level, with fewer clinical trials available for review. SARMs are currently being investigated mostly for use in prostate cancer at different stages, but hold promise for multiple other applications. Summary Recent clinical trials indicate that selective estrogen receptor modulators are useful in treatment of disorders of bone and mineral metabolism and breast cancer, and in reduction of cardiovascular risk factors. Selective androgen receptor modulators offer important benefits for management of prostate cancer at different stages, as well as other disorders.

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Section: Selective Androgen Receptor Modulatorsmentioning

confidence: 99%

New selective estrogen and androgen receptor modulators

Clarke

Khosla

2009

Current Opinion in Rheumatology

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“…The in vitro stability study was carried out in isolated whole rat blood following the procedure reported in the literature [39][40]44]. Around 93% of the radioactivity was Long circulation time is an important feature for radiopharmaceuticals since a large number of passages through the targeted areas might favor radiotracer accumulation leading to better target/non-target ratios.…”

Section: Biochemical Studiesmentioning

confidence: 99%

Synthesis and biodistribution of 1-[2-(cyclopentadienyltricarbonyltechnetium-99m)-2-oxo-ethoxy-phenyl]-1,2-di- (p-hydroxyphenyl)but-1-ene for tumor imaging

Dallagi

Saidi

Jaouen

et al. 2019

Journal of Organometallic Chemistry

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The high incidence and mortality of breast cancer and other estrogen receptor related tumors motivates efforts to develop innovative imaging probes to effectively diagnose, evaluate the extent of the tumor, and predict the efficacy of treatments while concurrently and selectively delivering anticancer agents to the cancer tissues. In the present study, 1-[2-(cyclopentadienyltricarbonyltechnetium-99m)-2-oxo-ethoxy-phenyl]-1,2-di-(phydroxyphenyl)but-1-ene was prepared and investigated as a potential agent for imaging estrogen receptors (ERs) in associated tumors. The compound was obtained in high 2 radiochemical purity and radiochemical yields. The biodistribution of the radioactive compound in mature female rats showed an ER-mediation in the ovarian target tissues as the uptake was reduced by a blocking dose of estradiol. The nonspecific uptake in muscle was relatively low.

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“…Tissue distribution studies with bicalutamide and hydantoin derivatives [136,143] showed that preferential accumulation of these drugs in anabolic tissues does not occur. Furthermore, although the conversion of testosterone to estrogen does play some role in the development of prostate disease, its contribution to the overall growth of the normal prostate is rather limited [144].…”

Section: Mechanisms Of Tissue Selectivitymentioning

confidence: 99%

Androgen Receptor

Dalton

Gao

2010

Nuclear Receptors

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Abstract:Androgen receptor (NR3C4, or AR) is another important steroid hormone receptor that is activated by endogenous androgens, mainly testosterone and 5α-dihydrotestosterone (5α-DHT). AR function can be regulated by the binding of its ligands, either agonists or antagonists, which initiate sequential conformational changes of the receptor that will affect receptor function. At the cellular level, AR mainly acts as a transcription factor to regulate downstream target genes expression, while emerging research also revealed that nongenomic actions contribute to AR signaling and function. AR mediates the physiological actions of androgen, which is responsible for male sexual differentiation and pubertal changes. Historically, various steroidal androgens were used to treat androgen-related endocrine disorders, but the advent of aromatase inhibitors and recombinant erythropoietin supplanted the use of androgens in many of these conditions. With the rapidly increasing knowledge of AR protein structure and molecular mechanism of action in the last few decades, a large variety of nonsteroidal ligands, have been developed to selectively modulate AR action with much improved tissue and/or function specificity and safety profiles as compared to steroids, which could greatly expand the therapeutic uses of androgens. This chapter will focus on the chemistry and structural biology of AR, and its role and potential as drug target in disease treatment, with emphasis on the recent development of selective androgen receptor modulators (SARMs). We will provide a brief introduction of AR structure and function, followed by a detailed discussion of well-characterized synthetic AR ligands (steroidal and nonsteroidal), with integrated discussions regarding the molecular mechanism of action and potential therapeutic applications for both existing and emerging classes of AR ligands.

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Synthesis and biological evaluation of a nonsteroidal bromine-76-labeled androgen receptor ligand 3-[76Br]bromo-hydroxyflutamide

Cited by 30 publications

References 39 publications

New selective estrogen and androgen receptor modulators

New selective estrogen and androgen receptor modulators

Synthesis and biodistribution of 1-[2-(cyclopentadienyltricarbonyltechnetium-99m)-2-oxo-ethoxy-phenyl]-1,2-di- (p-hydroxyphenyl)but-1-ene for tumor imaging

Androgen Receptor

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