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The synthesis of 7 alpha-methyl-substituted estrogens labeled with fluorine-18: potential breast tumor imaging agents.

Abstract：

:The 7 alpha-methyl substituent is reported to increase the binding affinity of estradiol for the estrogen receptor (ER). In order to evaluate whether this substituent would improve the in vitro binding characteristics and the in vivo tissue distribution of 18F labeled estrogens that we are developing as positron emission tomographic (PET) imaging agents for ER-positive breast tumors, we have prepared four 18F labeled analogs of 7 alpha-methylestradiol. These ligands were labeled in the 16 alpha or 16 beta position with 18F by nucleophilic displacement of the corresponding epimeric estrone trifluoromethanesulfonates with 18F fluoride ion. Lithium aluminum hydride reduction afforded the estradiol (E2) series, while lithium trimethylsilylacetylide addition provided the 17 alpha-ethynylestradiol (EE2) series. The decay-corrected yields were 2-35% for a synthesis time of 85 minutes for the E2 series, and 120 minutes for the EE2 series, and the effective specific activities were 158-1213 Ci/mmol. In nearly every case, the 7 alpha-methyl substituent increases ER binding affinity (measured at 25 C) and decreases binding to high affinity serum steroid binding proteins, alphafetoprotein, and sex steroid binding protein; this substituent, however, increases the lipophilicity and the predicted non-specific binding (estimated from octanol-water partition coefficients determined by reverse-phase high-pressure liquid chromatography/[HPLC]), with the result that the ratio of ER binding to non-specific binding is nearly the same for the 7 alpha-methyl substituted analogs as for the corresponding unsubstituted analogs. In vivo distribution studies demonstrated a high level of receptor-mediated uptake in receptor-rich target tissues (uterus, ovaries), and in some cases, other tissues with low ER titers (secondary target tissues, e.g., muscle, thymus) showed significant displaceable uptake, presumed to be receptor-mediated.(ABSTRACT TRUNCATED AT 250 WORDS)

journal_name

Steroids

journal_title

Steroids

authors

VanBrocklin HF,Liu A,Welch MJ,O'Neil JP,Katzenellenbogen JA

doi

10.1016/0039-128x(94)90043-4

subject

Has Abstract

pub_date

1994-01-01 00:00:00

pages

34-45

issue

eissn

0039-128X

issn

1878-5867

pii

0039-128X(94)90043-4

journal_volume

pub_type

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The synthesis of 7 alpha-methyl-substituted estrogens labeled with fluorine-18: potential breast tumor imaging agents.