Targeted Radiotherapy of Estrogen Receptor Positive Tumors

Technical Report · Thu Aug 31 04:00:00 EDT 2006

DOI:https://doi.org/10.2172/896748· OSTI ID:896748

Rajagopalan, Raghavan ^[1]

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1. Bioflexis

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.

• Research Organization: Bioflexis, LLC
• Sponsoring Organization: USDOE
• DOE Contract Number: FG02-05ER84274
• OSTI ID: 896748
• Report Number(s): DOE/ER/84274-1; DOE2005
• Country of Publication: United States
• Language: English

Related Subjects

08 HYDROGEN
AFFINITY
ESTRADIOL
ESTROGENS
GLOBULINS
HORMONES
HYDROGEN
IN VITRO
IN VIVO
NEOPLASMS
RADIOISOTOPES
RADIOPHARMACEUTICALS
RADIOTHERAPY
STABILITY
STEROIDS
TARGETS
TESTOSTERONE