Synthesis and evaluation of an N-[18F]fluorodeoxyglycosyl amino acid for PET imaging of tumor metabolism☆,☆☆,★
Introduction
The increase of energy metabolism and overexpression of specific receptors in various tumors are utilized in nuclear medicine for imaging with radiolabeled probes. Many receptors have been identified as promising targets for radiopharmaceutical development and successfully implemented in clinical research and routine practice [1]. Compared to imaging with receptor ligands, metabolic imaging probes do not reflect the expression of a specific molecule but provide information on the integrated function of multiple transporters and enzymes involved in a metabolic process [2]. Thus, metabolic imaging offers unique information on specific physiological function in tumor, which generally cannot be derived from gene expression profiles or immunohistochemistry [3].
Positron emission tomography (PET) is a non-invasive imaging technology that can detect and characterize tumors based on their molecular and biochemical properties [4]. Numerous studies prove that malignant tumors can be detected with high sensitivity and specificity by PET, which measures their increased metabolic rates of glucose, amino acids, or lipids [5]. 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) is by far the most widely used PET probe in oncology. However, the high uptake of [18F]FDG in non-tumor tissues, e.g. brain or inflammatory lesions, results in complications in the interpretation of imaging results [6,7], which necessitated the development of other types of PET imaging tracers.
Amino acid metabolism PET imaging is an important complement to the clinical applications of [18F]FDG imaging [8,9]. Increased radiolabeled amino acid transport in tumor cells results from overexpression of the transporter systems and is related to the alterations in tumor vasculature and tumor cell proliferation [10,11]. Meanwhile, radiolabeled amino acids can be more tumor specific, as their uptake is less influenced by inflammation [12,13]. Compared to [18F]FDG, radiolabeled amino acids offer significant improvement in the diagnostic evaluation of cerebral tumors and display adequate contrast as low cortical protein metabolism [14,15]. And radiolabeled amino acids have been recently recommended for the use of amino acid PET imaging for brain tumor in addition to MRI by the Response Assessment in Neuro-Oncology (RANO) working group [16].The previously most commonly used amino acid tracer L-[11C]methionine for PET is restricted to centers with onsite cyclotrons due the short half-life time of carbon-11, which now has been replaced in many centers with 18F-labelled amino acid tracers. The best established 18F-labelled amino acid tracers at present are 6-[18F]Fluoro-3,4-dihydroxy-L-phenylalanine ([18F]FDOPA) and 2-[18F]fluoroethyltyrosine ([18F]FET) [17].
The condensation of aldoses and amino compounds is one of the most prospective ways for the preparation of N-glycosides. The N-aryl-glycosides were prepared through the N-glycosylation of aromatic compounds starting from aniline derivatives and sugars with high reaction efficiency, followed by the rearrangement known as Amadori products. [18F]FDG, as the most popular probe for PET imaging, could be used as a prosthetic group for radiolabelling peptides [18], and a series of 18F-Fluorodeoxyglycosylamines were obtained from the N-glycosylation of amino compounds using [18F]FDG as the quasi-amadori rearrangement products [19]. In order to achieve the preparation of an 18F-labelled amino acid probe, the reaction of the N-glycosylation of aromatic compounds could be used. In the present study, we described the preparation of a small-molecule 18F-labelled glycoconjugate tracer ([18F]FDGly-NH-Phe) produced through a direct condensation reaction using [18F]FDG and L-4-aminophenylalanine (Scheme 1). We also evaluated the in vitro transport profile, biodistribution, and in vivo PET imaging performance of [18F]FDGly-NH-Phe and conducted comparison with those of [18F]FDG.
Section snippets
General
The 2-deoxy-2-[19F]fluoro-d-glucose ([19F]FDG) was purchased from Huayi Isotope Co. (Jiangsu, China). L-4-aminophenylalanine and Acetic Acid were obtained from Xilong Chemical Industry Co. (Guangdong, China). 2-Amino-2-norbornanecarboxylic acid (BCH), N-methyl-2-amino-isobutyric acid (MeAIB), and serine were purchased from Sigma-Aldrich (St. Louis MO, USA). All chemicals used in the synthesis were commercial products without further purification, unless otherwise stated. 1H and 13C Nuclear
Chemical synthesis
Non-radioactive [19F]FDGly-NH-Phe was synthesized in a coupling reaction between [19F]FDG and L-4-aminophenylalanine (Scheme 1). HPLC purification of [19F]FDGly-NH-Phe yielded approximately 35% (from 19F-FDG) of the desired product (Fig. S1A). The analytical HPLC chromatograms were presented in Fig. 1, which showed that the retention time of L-4-aminophenylalanine and [19F]FDGly-NH-Phe was 6.5 min and 7.5 min respectively. There was no ultraviolet absorption for [19F]FDG. The structural
Discussion
Given the pitfalls and limitations of [18F]FDG-specific tumors PET imaging, metabolic alteration of the tumor beyond enhanced glycolysis open the new opportunities to develop improved PET tracer alternatives for tumor imaging [[23], [24], [25]], which amino acid metabolism PET imaging is an important option to the clinical application of [18F]FDG imaging.
It's worth noting that the glycoconjugation was a valid strategy to improve the performance of certain anticancer drugs as the glucosylamines
Conclusions
In conclusion, [18F]FDGly-NH-Phe as an N-[18F]fluorodeoxyglycosyl amino acid was prepared using a direct condensation of [18F]FDG with L-4-aminophenylalanine. Both the in vitro tumor cell uptake and in vivo PET studies confirmed that [18F]FDGly-NH-Phe could be used for tumor metabolism imaging and demonstrated the feasibility for tumor specific imaging.
The following are the supplementary are related to this article.
Acknowledgments
This work was supported by the National Natural Science Foundation (No. 81571716, 81471695), the Science and Technology Planning Project of Shanxi Province (No. 2015091017).
References (41)
- et al.
Proportion of false-positive lesions at interim and end-of-treatment FDG-PET in lymphoma as determined by histology: systematic review and meta-analysis
Eur J Radiol
(2016) - et al.
Amino acid transport in tumor cells
Adv Cancer Res
(1965) - et al.
Synthesis and evaluation of O-(3-[18F]fluoropropyl)-L-tyrosine as an oncologic PET tracer
Nucl Med Biol
(2003) - et al.
Imaging of amino acid transport in brain tumours: positron emission tomography with O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET)
Methods
(2017) - et al.
Comparison of fluorotyrosines and methionine uptake in F98 rat gliomas
Nucl Med Biol
(2003) - et al.
Radiosynthesis and biological evaluation of N-(2-[(18)F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine as a PET tracer for oncologic imaging
Nucl Med Biol
(2017) - et al.
D-glucose- and D-mannose-based antimetabolites. Part 2. Facile synthesis of 2-deoxy-2-halo-D-glucoses and -D-mannoses
Carbohydr Res
(2009) - et al.
PET tracers beyond FDG in prostate Cancer
Semin Nucl Med
(2016) - et al.
Synthesis and evaluation of N-alkyl-beta-D-glucosylamines on the growth of two wood fungi, Coriolus versicolor and Poria placenta
Carbohydr Res
(2008) - et al.
One-pot stereoselective synthesis of β-N-aryl-glycosides by N-glycosylation of aromatic amines: application to the synthesis of tumor-associated carbohydrate antigen building blocks
Tetrahedron
(2007)
Adduct of 2-[18F]FDG and 2-nitroimidazole as a putative radiotracer for the detection of hypoxia with PET: synthesis, in vitro- and in vivo-characterization
Appl Radiat Isot
System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line
Cancer Lett
Cloning and functional expression of a human Na(+) and Cl(−)-dependent neutral and cationic amino acid transporter B(0+)
J Biol Chem
Evaluation of F-18-labeled amino acid derivatives and [18F]FDG as PET probes in a brain tumor-bearing animal model
Nucl Med Biol
Comparison of 18F-FDG, 18F-FET and 18F-FLT for differentiation between tumor and inflammation in rats
Nucl Med Biol
Synthesis and biological evaluation of N-(2-[(18)F]Fluoropropionyl)-L-methionine for tumor imaging
Nucl Med Biol
Development of PET probes for cancer imaging
Curr Top Med Chem
Positron emission tomography imaging of tumor cell metabolism and application to therapy response monitoring
Front Oncol
Novel approaches to imaging tumor metabolism
Cancer J
Imaging cancer metabolism
Biomol Ther
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