I.~fluorine-18 Labeled Corticosteroids and Progestins for Receptor-Based Imaging of the Brain and of Breast Tumors. II.~Synthesis and NMR Spectrum of (carbon-13(18))-Meso-Hexestrol
Kochanny, Monica Jean
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https://hdl.handle.net/2142/72279
Description
Title
I.~fluorine-18 Labeled Corticosteroids and Progestins for Receptor-Based Imaging of the Brain and of Breast Tumors. II.~Synthesis and NMR Spectrum of (carbon-13(18))-Meso-Hexestrol
Author(s)
Kochanny, Monica Jean
Issue Date
1993
Doctoral Committee Chair(s)
Katzenellenbogen, John A.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Abstract
The presence of steroid receptors in certain target tissues and tumors provides an avenue for monitoring pathological changes through the use of positron emission tomography and an appropriate fluorine-18 labeled ligand. We have prepared fluorinated analogs of six natural and synthetic corticosteroids as potential diagnostic imaging agents for Alzheimer's dementia. Four of these ligands have been prepared in fluorine-18 labeled form (three in high specific activity, 369-1618 Ci/mmol), by fluoride ion (n-Bu$\sb4$N$\sp $F) displacement of mesylate or triflate precursors. Tissue distribution studies in adrenalectomized, mature male rats showed no brain uptake for three compounds, while the fourth was taken up by the brain but did not selectively localize in target tissues (hippocampus, cortex). Two compounds showed partially competable uptake in the pituitary, suggesting that failure to cross the blood-brain barrier may limit distribution.
Fluoroacetophenone ketals of 16$\alpha,$17$\alpha,$21-trihydroxy-19-norprogesterone have been synthesized. One isomer was found to have high affinity for the progesterone receptor (PgR) and was evaluated as a potential imaging agent for receptor-positive breast tumors. The ketalization reaction was adapted to allow synthesis of the steroid ketal in fluorine-18 labeled form. Biodistribution in estrogen-primed immature female rats showed high selectivity for target tissue (uterus), with uterus/blood and uterus/muscle (non-target) ratios of 14 and 8 at 1 h and 38 and 28 at 3 h, respectively. Low activity levels in bone indicated metabolic stability of the radiolabel.
A number of other fluorine- and oxygen-substituted trihydroxynorprogesterone ketals have been prepared in an effort to produce a PgR ligand of lower lipophilicity than the fluoroacetophenide. Several of the fluorinated analogs showed high affinity for PgR, while none of the oxygen-substituted ketals had substantial affinity. The fluorinated ketals retained unfavorable lipophilicity properties.
The estrogen receptor ligand meso-hexestrol has been prepared fully substituted with carbon-13 as a ligand for NMR studies of the estrogen receptor. The $\sp $C NMR spectrum shows extensive carbon-carbon coupling and many non-first order coupling patterns. Carbon-carbon coupling constants have been determined through selective $\sp $C-decoupling along with iterative simulation of the resulting spectra.
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