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Title:Synthesis and evaluation of fluorine-18 labeled androgens as in vivo imaging agents for prostatic cancer using PET
Author(s):Liu, Aijun
Doctoral Committee Chair(s):Katzenellenbogen, John A.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Chemistry, Pharmaceutical
Health Sciences, Radiology
Chemistry, Nuclear
Abstract:In order to develop androgen receptor (AR) based probes for in vivo imaging of prostatic cancer using positron emission tomography (PET), four pairs of 16$\beta$- and 16$\alpha$-fluoro androgens, as well as two 20-fluoro androgens have been synthesized. The fluorination was achieved mainly by nucleophilic fluoride displacement of a triflate or a spirocyclic sulfate precursor, prepared by multistep synthesis.
Of the ten fluorinated androgens, 16$\beta$-F-DHT (1), 16$\beta$- and 16$\alpha$-F-Mib (5 and 6), 16$\beta$- and 16$\alpha$-F-MNT (7 and 8), 20-F-Mib (9), as well as 20-F-R1881 (10) were found to have high relative binding affinity for AR, 19%-53% of the potent androgen R1881. In most cases, the fluorination improved the binding selectivity of the androgens to AR vs. other steroid receptors and SBP, and the 16$\beta$-fluoro androgens have higher affinity than their corresponding 16$\alpha$-fluoro epimers. Other interesting structure-activity relationships were observed.
Seven of these fluorinated androgens have been prepared in fluorine-18 labeled form, and their in vivo tissue distribution have been studied in estrogen-treated mature male rats. All seven fluorine-18 labeled androgens showed selective and blockable target tissue uptake: the prostate to blood and prostate to muscle ratios (at 4 h) were from 5 (20-F-R1881) to 30 (16$\alpha$-F-MNT), and the uptake in the unblocked animals were 2.5 (16$\beta$-F-Mib) to 5.3 (16$\alpha$-F-MNT and 20-F-MIb) fold higher than that in the blocked animals. Rapid in vivo defluorination was observed with three 16$\beta$-fluoro androgens (1, 3 and 7). Thus, we have synthesized the first fluorine-18 labeled androgens that have relative high binding affinity and selectivity for AR, and show selective target tissue uptake. It appears that 16$\beta$-F-F-Mib (5), 16$\alpha$-F-MNT (8) and 20-F-Mib (9) are the most promising candidates as in vivo imaging agents for prostatic cancer.
Issue Date:1991
Rights Information:Copyright 1991 Liu, Aijun
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9210898
OCLC Identifier:(UMI)AAI9210898

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