Optimization of the alkyl side chain length of fluorine-18-labeled 7α-alkyl-fluoroestradiol
| Autor: | Mayumi Okamoto, Kiichi Ishiwata, Jun Toyohara, Hiromitsu Shibayama, Kyosuke Naka, Isao Shimizu, Yuya Kitagawa |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Fluorine Radioisotopes
Cancer Research Halogenation Stereochemistry chemistry.chemical_element Estrogen receptor 01 natural sciences 030218 nuclear medicine & medical imaging Mice 03 medical and health sciences 0302 clinical medicine In vivo Animals Structure–activity relationship Tissue Distribution Radiology Nuclear Medicine and imaging Fluoroethyl Alkyl chemistry.chemical_classification Radiochemistry Estradiol 010405 organic chemistry Metabolism In vitro 0104 chemical sciences Receptors Estrogen chemistry Isotope Labeling Fluorine Molecular Medicine Female |
| Zdroj: | Nuclear Medicine and Biology. 43:512-519 |
| ISSN: | 0969-8051 |
| DOI: | 10.1016/j.nucmedbio.2016.05.008 |
| Popis: | 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 IC 50 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-A ligand binding cavities of ERα are suitable for 7α-fluoroalkylestradiol derivatives. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect