Synthesis of 16α-[125I]iodo-5α-dihydrotestosterone and evaluation of its affinity for the androgen receptor

Hoyte, Robert M.; Rosner, William; Hochberg, Richard B.

doi:10.1016/0022-4731(82)90097-8

Cited by 17 publications

(13 citation statements)

References 21 publications

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“…Gamma-emitting radionuclides ( 77 Br, 82 Br, 125 I, 175 Se) have been used to radiolabel androgen derivatives for potential application as AR imaging agents; however, these ligands were problematic, with metabolic elimination of the radionuclide, low affinity, and poor specific activity. [51][52][53][54][55] In keeping with previous observations from the development of ER imaging agents, PET isotopes provided the scope for superior quantification compared to SPECT isotopes. Liu and colleagues synthesized six 18 F-radiolabeled androgens as potential ligands for imaging prostate cancer and determined their tissue distribution in diethylstilbestroltreated male rats.…”

Section: Ar Radioligandsmentioning

confidence: 73%

PET Imaging of Steroid Hormone Receptor Expression

et al. 2015

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Steroid hormone receptor (SHR) expression and changes in SHR expression compared to basal levels, whether upregulated, downregulated, or mutated, form a distinguishing feature of some breast, ovarian, and prostate cancers. These receptors act to induce tumor proliferation. In the imaging context, total expression together with modulation of expression can yield predictive and prognostic information. Currently, biopsy for histologic assessment of SHR expression is routine for breast and prostate cancer; however, the technique is not well suited to the heterogeneous tumor environment and can lead to incorrect receptor expression assignment, which precludes effective treatment. The development of positron emission tomography (PET) radioligands to image receptor expression may overcome the difficulties associated with tumor heterogeneity and facilitate the assessment of metastatic disease.

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Section: Ar Radioligandsmentioning

confidence: 73%

PET Imaging of Steroid Hormone Receptor Expression

et al. 2015

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“…been a widely used radioiodinated probe for ER,13 while 17 -((E)-[125I]iodovinyl)-19-nortestosterone and 17a-(6'-[ 125I] iodohexl'-ynyl)-19-nortestosterone have been successfully used for assaying PgR.14•15 Unfortunately, however, development of a radioiodinated probe for AR has not been so successful; 17/3-hydroxy-16a-iodo-5aandrostanol-3-one, prepared by analogy to the corresponding estrogenic ligand, did not show any significant activity toward AR. 5 We therefore undertook synthesis of potential halogenated androgen ligands which could be radioiodinated, including both 5a-DHT and 19-nortestosterone analogues. 5a-DHT Analogues.…”

Section: Resultsmentioning

confidence: 99%

A potential radioiodinated ligand for androgen receptor: 7.alpha.-methyl-17.alpha.-[2'-(E)-iodovinyl]-19-nortestosterone

Salman

Chamness²

1991

J. Med. Chem.

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The presence of androgen receptor (AR) in prostate cancer has been linked to the androgen-dependent nature of the tumor and has also been shown to have prognostic significance; it also appears to be a positive prognostic indicator in breast cancer. However, due to the relatively low AR concentrations in most tumors and the inherently low specific activity of tritium, the assay of AR based on available 3H-ligands is not sensitive enough to measure accurately the amount of receptor in small specimens. A 125I-ligand like those available for the estrogen and progesterone receptors would be helpful, but development of such a ligand for AR has not been very successful. Although several androgen analogues containing iodine, bromine, or selenium have been synthesized specifically as potential probes for AR, none have shown any significant affinity or specificity for the receptor. We therefore undertook the synthesis of new potential AR ligands which could be radioiodinated, and determined their affinities for AR (from rat uterus and MCF-7 human breast cancer cells) by using a competition assay. We have examined both 5 alpha-dihydrotestosterone (5 alpha-DHT) and 19-nortestosterone analogues and have identified two such compounds which showed high AR affinity: (17 alpha,20E)-17 beta-hydroxy-21-iodo-5 alpha-pregn-20-en-3-one (17 alpha-[E)-iodovinyl)-5 alpha-DHT, 9) and 17 beta-hydroxy-7 alpha-methyl-(17 alpha,20E)-21-iodo-19-norpregna-4,20-dien-3- one (7 alpha-methyl-17 alpha-[E)-iodovinyl)-19-nortestosterone, 11). In fact, the affinity of the latter for human AR was found to be superior to that of 5 alpha-DHT itself. These iodovinyl analogues could be easily prepared in the radioiodinated form, and should prove to be extremely useful in assaying low levels of AR in small specimens.

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“…This mostly represented an extension of studies conducted during the late 1980's in which radiohalogens 1-125 or F-18 were incorporated at the 7a, 16a, or 17a-positions (Fig. 8) [30][31][32][33]. These early results were generally disappointing in that the radiochemicals exhibited either little specific binding or metabolic lability, or both.…”

Section: Androgen Receptor Ligandsmentioning

confidence: 87%

A Structure Based, Solid Phase Synthesis Approach to the Development of Novel Selective Estrogen Receptor Modulatory Steroids

Hanson¹

2001

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the lime for reviewing instructions, searching existing data sources, gathering and maintaining ' the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503 REPORT DOCUMENTATION PAGE REPORT TYPE AND DATES COVEREDAnnual (1 Jun 99 -31 May 00) TITLE AND SUBTITLEA Structure Based, Solid Phase Synthesis Approach to the Development of Novel Selective Estrogen Receptor Modulatory Steroids AUTHOR(S)Robert Hanson, Ph.D. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Northeastern University Boston, Massachusetts 02115 E-MAIL:r.hanson@nunet.neu. edu The objective of this project is the development of new chemotherapeutic agents for the treatment of hormone responsive breast cancer using a structure-based, solid-phase synthesis approach. We have successfully linked an activated derivative of estradiol to a solid support and converted it to two different series of estrogen receptor ligands. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)UWe have begun the biological evaluation of these compounds and initail results suggest that significant receptor affinity is retained.Conformational studies using NMR and computational methods have provided results that can be used in directing the synthesis of newer estrogen receptor binding agents. Where copyrighted material is quoted, permission has been tained to use such material. SUBJECT TERMSWhere material from documents designated for limited distribution is quoted, permission has been obtained to use the material.Citations of commercial organizations and trade names in this report do not constitute an official Department of Army endorsement or approval of the products or services of these organizations.N/A In conducting research using animals, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory S.Introduction:The overall objective of this project is the development of new chemotherapeutic agents for the treatment of hormone responsive breast cancer. Based upon our previous synthetic work and molecular modeling studies we selected the 17a-(substituted phenyl)vinyl estradiols as the lead compounds for our drug development program. We chose a solid-phase synthesis approach to more rapidly generate target compounds for subsequent bioevaluation studies. The review of the results and comparison with molecular conformations, determined by both computational and analytical methods, would provide insight into the interactions of the compounds with the target estrogen receptors. Our approach involved developing the solid phas...

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Synthesis of 16α-[125I]iodo-5α-dihydrotestosterone and evaluation of its affinity for the androgen receptor

Cited by 17 publications

References 21 publications

PET Imaging of Steroid Hormone Receptor Expression

PET Imaging of Steroid Hormone Receptor Expression

A potential radioiodinated ligand for androgen receptor: 7.alpha.-methyl-17.alpha.-[2'-(E)-iodovinyl]-19-nortestosterone

A Structure Based, Solid Phase Synthesis Approach to the Development of Novel Selective Estrogen Receptor Modulatory Steroids

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