Regular articleComparison of fluorotyrosines and methionine uptake in F98 rat gliomas
Introduction
Radiolabeled amino acids and PET show great potential for more accurate diagnosis of cerebral gliomas [8], [15]. Although MRI provides detailed morphologic information in patients with cerebral gliomas, some reports showed that tumoral heterogeneity of glioma is not always adequately reflected on MR images (9). Various PET studies have shown that accumulation of [11C]Methyl-L-methionine (11C-MET) correlates with histological tumor spread [20], [21]. 18F-labeled amino acids are an attractive alternative to MET due to the longer lived 18F (110 min half-life) which offers logistic advantages compared to 11C (20 min half-life).
A number of attempts were successful to label amino acids with 18F (for review see 3, 18) but only some of these unphysiological amino acids exhibit protein incorporation e.g. , 2-[18F]fluoro-L-tyrosine (FTyr)( 4). The amino acid derivative O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is not incorporated into protein (27) but can be produced with high radiochemical yields due to nucleophilic substitution and thus offers practical advantages for routine clinical practice (10). Initial studies in patients with cerebral gliomas demonstrated similar results compared with 11C-MET PET (26) and a better delineation of tumor extent compared to MRI (22).
The aim of this study was to compare the transport mechanisms, protein incorporation and tumor imaging of the unphysiological amino acids FET and FTyr in relation to MET in a rat glioma model. For comparison MET was chosen since most clinical experience in gliomas was gained with PET and 11C-MET. Dual tracer autoradiography allowed an accurate comparison of T/B ratios, of intratumoral tracer distribution and of histological tumor extent.
Section snippets
Radiopharmaceuticals
The amino acid derivative O-(2-[18F]fluoroethyl)-L-tyrosine was produced via aminopolyether supported nucleophilic 18F-fluorination of N-trityl-O-(2-tosyl-oxyethyl)-L-tyrosine tert.butylester with a specific activity of >20 TBq/mmol (5).
Carrier added 2-[18F]Fluoro-L-tyrosine was prepared by electrophilic fluoro-de-stannylation of the newly developed ethylester of N,O-di-Boc-2-trimethylstannyl-L-tyrosine with a specific activity of >70 GBq/mmol as described in detail (7). After deprotection
Transport experiments
To investigate whether uptake of MET, FET and FTyr is mediated by the same or different sets of transporters we studied uptake of all three compounds in the presence of competing amounts of amino acids and inhibitors, and in presence or absence of Na+ (cf. Fig. 1, Fig. 2, Fig. 3).
The transport characteristics of all tracers were very similar in this cell line. In presence of the amino acid transport system A inhibitor MeAIB (20 mM) no significant effect on uptake was observed. BCH (10 mM),
Discussion
In our experiments transport characteristics of MET, FET and FTyr appeared to be very similar. The lack of inhibitory effects of MeAIB on the transport of all these tracers excludes a significant role of system A like transport for these tracers. A relevant expression of system A like amino acid transport in F98 glioma cells has been observed in previous experiments using proline analogues (17).
Transport of MET, FET and FTyr in F98 glioma cells consists of a Na+-dependent activity of ca. 70%
Conclusion
Transport characteristics of MET, FET and FTyr in F98 gliomas are nearly identical. MET and FTyr are incorporated into protein in contrast to FET but tumor imaging is similar. Due to logistical advantages in production FET appears presently one of the most promisings tracer for neurooncology.[3], [18]
Acknowledgements
The authors wish to thank Mrs. Regina König and Mrs. Elke Joussen for assistance in cell culture experiments, Mr. Markus Cremer and Mr. Norbert Hartwigsen for assistance in animal experiments, Mrs. Silke Grafmüler, Mrs. Bettina Palm and Mrs. Erika Wabbals and Mrs. Elke Hess for assistance in the radiosynthesis of FET and FTyr.
This work was supported by the Deutsche Forschungsgemeinschaft (Grant La-1263/1-1).
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