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Title: Targeted Radiotherapy of Estrogen Receptor Positive Tumors

Abstract

The overall objectives of the proposal were to develop estrogen receptor (ER) binding small molecule radiopharmaceuticals for targeted radiotherapy of ER positive (ER+) tumors. In particular, this proposal focused on embedding a {sup 186,188}Re or a {sup 32}P radionuclide into an estrogen steroidal framework by isosteric substitution such that the resulting structure is topologically similar to the estrogen (estrogen mimic). The estrogen mimic molecules expected to bind to the ER and exhibit biodistribution akin to that of native estrogen due to structural mimicry. It is anticipated that the {sup 186,188}Re- or a {sup 32}P-containing estrogen mimics will be useful for targeted molecular radiotherapy of ER+ tumors. It is well established that the in vivo target tissue uptake of estrogen like steroidal molecules is related to the binding of the steroids to sex hormone binding globulin (SHBG). SHBG is important in the uptake of estrogens and testosterone in target tissues by SHBG receptors on the cell surface. However, hitherto the design of estrogen like small molecule radiopharmaceuticals was focused on optimizing ER binding characteristics without emphasis on SHBG binding properties. Consequently, even the molecules with good ER affinity in vitro, performed poorly in biodistribution studies. Based on molecular modeling studies themore » proposal focused on developing estrogen mimics 1-3 which were topologically similar to native estrogens, and form hydrogen bonds in ER and SHBG in the same manner as those of native estrogens. To this end the technical objectives of the proposal focused on synthesizing the rhenium-estrone and estradiol mimics 1 and 2 respectively, and phosphorous estradiol mimic 3 and to assess their stability and in vitro binding characteristics to ER and SHBG.« less

Authors:
Publication Date:
Research Org.:
Bioflexis, LLC
Sponsoring Org.:
USDOE
OSTI Identifier:
896748
Report Number(s):
DOE/ER/84274-1
DOE2005; TRN: US200718%%64
DOE Contract Number:
FG02-05ER84274
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
08 HYDROGEN; AFFINITY; ESTRADIOL; ESTROGENS; GLOBULINS; HORMONES; HYDROGEN; IN VITRO; IN VIVO; NEOPLASMS; RADIOISOTOPES; RADIOPHARMACEUTICALS; RADIOTHERAPY; STABILITY; STEROIDS; TARGETS; TESTOSTERONE

Citation Formats

Raghavan Rajagopalan. Targeted Radiotherapy of Estrogen Receptor Positive Tumors. United States: N. p., 2006. Web. doi:10.2172/896748.
Raghavan Rajagopalan. Targeted Radiotherapy of Estrogen Receptor Positive Tumors. United States. doi:10.2172/896748.
Raghavan Rajagopalan. Thu . "Targeted Radiotherapy of Estrogen Receptor Positive Tumors". United States. doi:10.2172/896748. https://www.osti.gov/servlets/purl/896748.
@article{osti_896748,
title = {Targeted Radiotherapy of Estrogen Receptor Positive Tumors},
author = {Raghavan Rajagopalan},
abstractNote = {The overall objectives of the proposal were to develop estrogen receptor (ER) binding small molecule radiopharmaceuticals for targeted radiotherapy of ER positive (ER+) tumors. In particular, this proposal focused on embedding a {sup 186,188}Re or a {sup 32}P radionuclide into an estrogen steroidal framework by isosteric substitution such that the resulting structure is topologically similar to the estrogen (estrogen mimic). The estrogen mimic molecules expected to bind to the ER and exhibit biodistribution akin to that of native estrogen due to structural mimicry. It is anticipated that the {sup 186,188}Re- or a {sup 32}P-containing estrogen mimics will be useful for targeted molecular radiotherapy of ER+ tumors. It is well established that the in vivo target tissue uptake of estrogen like steroidal molecules is related to the binding of the steroids to sex hormone binding globulin (SHBG). SHBG is important in the uptake of estrogens and testosterone in target tissues by SHBG receptors on the cell surface. However, hitherto the design of estrogen like small molecule radiopharmaceuticals was focused on optimizing ER binding characteristics without emphasis on SHBG binding properties. Consequently, even the molecules with good ER affinity in vitro, performed poorly in biodistribution studies. Based on molecular modeling studies the proposal focused on developing estrogen mimics 1-3 which were topologically similar to native estrogens, and form hydrogen bonds in ER and SHBG in the same manner as those of native estrogens. To this end the technical objectives of the proposal focused on synthesizing the rhenium-estrone and estradiol mimics 1 and 2 respectively, and phosphorous estradiol mimic 3 and to assess their stability and in vitro binding characteristics to ER and SHBG.},
doi = {10.2172/896748},
journal = {},
number = ,
volume = ,
place = {United States},
year = {Thu Aug 31 00:00:00 EDT 2006},
month = {Thu Aug 31 00:00:00 EDT 2006}
}

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