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



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.



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.



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.
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; Research Institute for Science and Engineering, Waseda University, Tokyo, Japan.
Mayumi
M
Okamoto
School of Advanced Science and Engineering, Waseda University, Tokyo, Japan; Fine Organic Chemistry, Institute for Chemical Research, Kyoto University, Kyoto, Japan.
Hiromitsu
H
Shibayama
School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Kyosuke
K
Naka
School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Yuya
Y
Kitagawa
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.
Kiichi
K
Ishiwata
School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Isao
I
Shimizu
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. Electronic address: toyohara@pet.tmig.or.jp.
Jun
J
Toyohara
D000818:Animals; D004958:Estradiol / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes; D054879:Halogenation; D007553:Isotope Labeling; D051379:Mice; D011854:Radiochemistry; D011960:Receptors, Estrogen / Q000378:metabolism; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D011960:Receptors, Estrogen; D004958:Estradiol
C-7α-[(18)F]FES; Estrogen receptor; Positron emission tomography; Structure–activity relationship