Optimization of the alkyl side chain length of fluorine-18-labeled 7α-alkyl-fluoroestradiol

Mayumi Okamoto; Hiromitsu Shibayama; Kyosuke Naka; Yuya Kitagawa; Kiichi Ishiwata; Isao Shimizu; Jun Toyohara

doi:10.1016/j.nucmedbio.2016.05.008

Optimization of the alkyl side chain length of fluorine-18-labeled 7α-alkyl-fluoroestradiol

Nucl Med Biol. 2016 Aug;43(8):512-9. doi: 10.1016/j.nucmedbio.2016.05.008. Epub 2016 May 28.

Authors

Mayumi Okamoto¹, Hiromitsu Shibayama², Kyosuke Naka³, Yuya Kitagawa³, Kiichi Ishiwata⁴, Isao Shimizu³, Jun Toyohara⁵

Affiliations

¹ Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; Research Institute for Science and Engineering, Waseda University, Tokyo, Japan.
² School of Advanced Science and Engineering, Waseda University, Tokyo, Japan; Fine Organic Chemistry, Institute for Chemical Research, Kyoto University, Kyoto, Japan.
³ School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
⁴ Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; Institute for Cyclotron and Drug Discovery Research, Southern Tohoku Research Institute of Neuroscience, Koriyama, Japan; Department of Biofunctional Imaging, Fukushima Medical University, Fukushima, Japan.
⁵ Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. Electronic address: toyohara@pet.tmig.or.jp.

PMID: 27289329
DOI: 10.1016/j.nucmedbio.2016.05.008

Abstract

Introduction: Several lines of evidence suggest that 7α-substituted estradiol derivatives bind to the estrogen receptor (ER). In line with this hypothesis, we designed and synthesized (18)F-labeled 7α-fluoroalkylestradiol (Cn-7α-[(18)F]FES) derivatives as molecular probes for visualizing ERs. Previously, we successfully synthesized 7α-(3-[(18)F]fluoropropyl)estradiol (C3-7α-[(18)F]FES) and showed promising results for quantification of ER density in vivo, although extensive metabolism was observed in rodents. Therefore, optimization of the alkyl side chain length is needed to obtain suitable radioligands based on Cn-7α-substituted estradiol pharmacophores.

Methods: We synthesized fluoromethyl (23; C1-7α-[(18)F]FES) to fluorohexyl (26; C6-7α-[(18)F]FES) derivatives, except fluoropropyl (C3-7α-[(18)F]FES) and fluoropentyl derivatives (C5-7α-[(18)F]FES), which have been previously synthesized. In vitro binding to the α-subtype (ERα) isoform of ERs and in vivo biodistribution studies in mature female mice were carried out.

Results: The in vitro IC50 value of Cn-7α-FES tended to gradually decrease depending on the alkyl side chain length. C1-7α-[(18)F]FES (23) showed the highest uptake in ER-rich tissues such as the uterus. Uterus uptake also gradually decreased depending on the alkyl side chain length. As a result, in vivo uterus uptake reflected the in vitro ERα affinity of each compound. Bone uptake, which indicates de-fluorination, was marked in 7α-(2-[(18)F]fluoroethyl)estradiol (C2-7α-[(18)F]FES) (24) and 7α-(4-[(18)F]fluorobutyl)estradiol (C4-7α-[(18)F]FES) (25) derivatives. However, C1-7α-[(18)F]FES (23) and C6-7α-[(18)F]FES (26) showed limited uptake in bone. As a result, in vivo bone uptake (de-fluorination) showed a bell-shaped pattern, depending on the alkyl side chain length. C1-7α-[(18)F]FES (23) showed the same levels of uptake in uterus and bone compared with those of 16α-[(18)F]fluoro-17β-estradiol.

Conclusions: The optimal alkyl side chain length of (18)F-labeled 7α-fluoroalkylestradiol was the shortest: C1-7α-[(18)F]FES. Our results indicate that shorter chain lengths within the 4-Å ligand binding cavities of ERα are suitable for 7α-fluoroalkylestradiol derivatives.

Keywords: C-7α-[(18)F]FES; Estrogen receptor; Positron emission tomography; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Estradiol / chemistry*
Estradiol / metabolism
Estradiol / pharmacokinetics
Female
Fluorine Radioisotopes*
Halogenation
Isotope Labeling
Mice
Radiochemistry
Receptors, Estrogen / metabolism
Tissue Distribution

Substances

Fluorine Radioisotopes
Receptors, Estrogen
Estradiol