Metabolism of no-carrier-added 2-[18F]fluoro-L-tyrosine in rats

Background: Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among these, 2-[18F]fluoro-L-tyrosine (2-[18F]Tyr) has been studied in mice at a low specific activity. Its incorporation into proteins is fast and metabolism via other pathways is limited. The present in vivo study was carried out in normal awake rats using no-carrier-added 2-[18F]Tyr. Under normal physiological conditions, we have studied the incorporation into proteins and the metabolism of the tracer in different brain areas. Methods: No-carrier-added 2-[18F]Tyr was administered to awake rats equipped with chronic arterial and venous catheters. The time course of the plasma activity was studied by arterial blood sampling. The biodistribution of the activity in the main organs was studied at the end of the experiment. The distribution of radioactive species in plasma and brain regions was studied by acidic precipitation of the proteins and HPLC analysis of the supernatant. Results: The absolute uptake of radioactivity in brain regions was homogenous. In awake rats, nocarrier-added 2-[18F]Tyr exhibits a fast and almost quantitative incorporation into the proteins fractions of cerebellum and cortex. In striatum, this incorporation into proteins and the unchanged fraction of the tracer detected by HPLC could be lower than in other brain regions. Conclusion: This study confirms the potential of 2-[18F]fluoro-L-tyrosine as a tracer for the assessment of the rate of protein synthesis by positron emission tomography. The observed metabolism suggests a need for a correction for the appearance of metabolites, at least in plasma

NO-CARRIER-ADDED (NCA) ARYL [F-18] FLUORIDES VIA THE NUCLEOPHILIC AROMATIC-SUBSTITUTION OF ELECTRON-RICH AROMATIC RINGS

Nucleophilic aromatic substitution by [18F]fluoride ion has been demonstrated on rings containing electron donating groups in addition to the necessary electron withdrawing and leaving groups

Fully automated radiosynthesis of N1-[18F]fluoroethyl-tryptophan and study of its biological activity as a new potential substrate for indoleamine 2,3-dioxygenase PET imaging

Introduction Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial step in the catabolism of l-tryptophan along the kynurenine pathway and exerts immunosuppressive properties in inflammatory and tumor tissues by blocking locally T-lymphocyte proliferation. Recently, 1-(2-[19F]fluoroethyl)-dl-tryptophan (1-[19F]FE-dl-Trp) was reported as a good and specific substrate of this enzyme. Herein, the radiosynthesis of its radioactive isotopomer (1-[18F]FE-dl-Trp, dl-[18F]5) is presented along with in vitro enzymatic and cellular uptake studies. Methods The one-pot n.c.a. radiosynthesis of this novel potential PET imaging tracer, including HPLC purification and formulation, has been fully automated on a FASTlab™ synthesizer. Chiral separation of both isomers and their formulation were implemented on a second cassette. In vitro enzymatic and cellular uptake studies were then conducted with the d-, l- and dl-radiotracers. Results The radiolabeling of the tosylate precursor was performed in DMF (in 5 min; RCY: 57% (d.c.), n = 3). After hydrolysis, HPLC purification and formulation, dl-[18F]5 was obtained with a global radiochemical yield of 18 ± 3% (not decay corrected, n = 7, in 80 min) and a specific activity of 600 ± 180 GBq/μmol (n = 5). The subsequent separation of l- and d-enantiomers was performed by chiral HPLC and both were obtained after formulation with an RCY (d.c.) of 6.1% and 5.8%, respectively. In vitro enzymatic assays reveal that l-[18F]5 is a better substrate than d-[18F]5 for human IDO. In vitro cellular assays show an IDO-specific uptake of the racemate varying from 30% to 50% of that of l-[18F]5, and a negligible uptake of d-[18F]5. Conclusion In vitro studies show that l-[18F]5 is a good and specific substrate of hIDO, while presenting a very low efflux. These results confirm that l-[18F]5 could be a very useful PET radiotracer for IDO expressing cells in cancer imaging