Positron emission tomography (PET) imaging is a useful method to evaluate in situ estrogen receptor (ER) status for the early diagnosis of breast cancer and optimization of the appropriate treatment strategy. The 18F-labeled estradiol derivative has been successfully used to clinically assess the ER level of breast cancer. In order to simplify the radiosynthesis process, one-step 18F-19F isotope exchange reaction was employed for the 18F-fluorination of the tracer of
Breast cancer has become the most common malignancy in women and the incidence of breast cancer is increasing over the world [
Positron emission tomography (PET) as an efficient noninvasive imaging technology has been applied successfully in clinic to provide the possibility for assessing the entire lesion and highly sensitive images of cancer diseases. Fluorine-18 is the most widely used radioisotope because of its ideal nuclear properties, such as low positron energy (0.64 MeV) and suitable physical half-life (109.8 min). Some fluorine-18-labeled estradiol derivatives, such as 16
Recently, Liu and coworkers have developed a one-step 18F-labeling method with high radiochemical yield and high specific activity [
Encouraged by the previous studies [
All the materials were purchased from Energy Chemical and were all of reagent grade or analytical grade without further purification. Flouride-18 was obtained from a medical cyclotron (HM7, Sumitomo Heavy Industries) through a bombardment of 18O-enriched water. Human breast cancer cell lines T47D and MCF-7 were purchased from the Cell Bank of Chinese Academy of Sciences (Shanghai, China) and cultured in the 1640 medium and
The semi-prep HPLC (Waters, USA) with a Waters 2998 photodiode array detector (PDA) and C18 HPLC column (5
The gradient elution condition for semi-prep HPLC analysis of
Time (min) | Flow (mL/min) | % A | % B |
---|---|---|---|
0.01 | 3.00 | 80.0 | 20.0 |
3.00 | 3.00 | 80.0 | 20.0 |
15.00 | 3.00 | 65.0 | 35.0 |
20.00 | 3.00 | 65.0 | 35.0 |
25.00 | 3.00 | 50.0 | 50.0 |
30.00 | 3.00 | 30.0 | 70.0 |
35.00 | 3.00 | 10.0 | 90.0 |
40.00 | 3.00 | 80.0 | 20.0 |
The analytical HPLC equipped with a C18 column (5
The gradient elution condition of analytical HPLC.
Time (min) | Flow | % A | % B |
---|---|---|---|
0.01 | 1.00 | 80.0 | 20.0 |
3.00 | 1.00 | 80.0 | 20.0 |
25.00 | 1.00 | 30.0 | 70.0 |
30.00 | 1.00 | 80.0 | 20.0 |
Nuclear magnetic resonance spectrometers (1H-NMR, 13C-NMR, and 19F-NMR, Bruker DRX-400, Bruker, Germany) were used to obtain spectra of samples dissolved in
Compound
Compound
Compound
The suspension of compound
Compound
Compound
Click chemistry was used for the synthesis of compound
The stability of the cold compound
Traditional 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess the cytotoxicity of
Fluoride-18 (100–300 mCi) produced by cyclotron was trapped on an anion-exchange resin and then eluted with pyridazine-HCl buffer (200
Octanol (50 mL) and distilled water (50 mL, pH 7.0) were mixed by oscillation at 25°C for 24 h. After standing, a separatory funnel was used to separate the two layers. The tracer (30
The cell uptake and block studies of the radiotracer
Small animal PET imaging was performed on an Inveon micro-PET scanner (Siemens Medical Solutions, Germany). Imaging studies were carried out on female Balb/c nude mice bearing the human breast cancer cell line MCF-7. The mice were anesthetized with 1.5%–2% isoflurane, positioned prone, immobilized, injected with
The harsh radiosynthesis conditions and purification procedure limit the clinical applications of the estradiol-based PET imaging agents. Thus, development of new radiolabeling method is imperative. In our previous work, a novel PET tracer
The synthetic route of
Synthesis route of
HPLC chromatogram of the precursor
Since the one-step 18F-19F isotope exchange labeling reaction was performed in the pyridazine-HCl buffer (pH = 2.0–2.5) around 80°C, the stability of
Stability of
The good biocompatibility is essential for the application of a PET imaging agent [
Cytotoxicity of
18F-labeling of the precursor
Radiochemical yield (RCY) of
Radio-HPLC analysis of
In order to evaluate the stability of
In vitro stability test of
The octanol-water partition coefficient (
Since estrogen receptor is overexpressed in human breast cancer cell lines MCF-7 and T47D, cell uptake and block studies of
Cell uptake and block studies of
In vivo micro-PET imaging was also carried out to investigate the specificity of
(a) Micro-PET imaging of
In summary, a novel estradiol-based PET imaging agent
The authors declare that there are no conflicts of interest regarding the publication of this paper.
Hongbo Huang and Ke Li contributed equally to this work.
This work was financially supported by Natural Science Foundation of China (21371082), Natural Science Foundation of Jiangsu Province (BK20151118), 333 Project of Jiangsu Province (BRA2016518), and Key Youth Medical Talent Project of Jiangsu Province (QNRC20162016626 and QNRC20162016629).
Supplementary date available: ESI-MS and NMR spectra. Figure S1: ESI-MS of compound