Synthesis and evaluation of ¹⁸F labeled FET prodrugs for tumor imaging.

Abstract

INTRODUCTION:

O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET, [(18)F]1) is a useful amino-acid-based imaging agent for brain tumors. This paper reports the synthesis and evaluation of three FET prodrugs, O-(2-[(18)F]fluoroethyl)-L-tyrosyl-L-glycine (FET-Gly, [(18)F]2), O-(2-[(18)F]fluoroethyl)-L-tyrosyl-L-alanine (FET-Ala, [(18)F]3) and N-acetyl O-(2-[(18)F]fluoroethyl)-L-tyrosine (AcFET, [(18)F]4), which could be readily hydrolyzed to FET in vivo for tumor imaging. We investigated their metabolism in the blood and imaging properties in comparison to FET ([(18)F]1).

METHODS:

Three new [(18)F]FET derivatives, 2-4, were prepared from their corresponding tosylate-precursors through nucleophilic fluorination and subsequent deprotection reactions. In vitro uptake studies were carried out in 9L glioma cancer cell lines. In vitro and in vivo hydrolysis studies were conducted to evaluate the hydrolysis of FET prodrugs in blood and in Fisher 344 rats. Biodistribution and PET imaging studies were then performed in rats bearing 9L tumors.

RESULTS:

New FET prodrugs were prepared with 3-28% decay corrected radiochemical yields, good enantiomeric purity (>95%) and high radiochemical purity (>95%). FET-Gly ([(18)F]2), FET-Ala ([(18)F]3), and AcFET ([(18)F]4) exhibited negligible uptake in comparison to the high uptake of FET ([(18)F]1) in 9L cells. Metabolism studies of FET-Gly ([(18)F]2), FET-Ala ([(18)F]3), and AcFET ([(18)F]4) in rat and human blood showed that FET-Ala ([(18)F]3) was hydrolyzed to FET ([(18)F]1) faster than FET-Gly ([(18)F]2) or AcFET ([(18)F]4). Most of the FET-Ala (79%) was converted to FET ([(18)F]1) within 5min in blood in vivo. Biodistribution studies demonstrated that FET-Ala ([(18)F]3) displayed the highest tumor uptake. The tumor-to-background ratios of FET-Ala ([(18)F]3) and FET ([(18)F]1) were comparable and appeared to be better than those of FET-Gly ([(18)F]2) and AcFET ([(18)F]4). PET imaging studies showed that both FET ([(18)F]1) and FET-Ala ([(18)F]3) could visualize tumors effectively, and that they share similar imaging characteristics.

CONCLUSIONS:

FET-Ala ([(18)F]3) demonstrated promising properties as a prodrug of FET ([(18)F]1), which could be used in PET imaging of tumor amino acid metabolism.

• Authors: Limin Wang, Brian P Lieberman, Karl Ploessl, Hank F Kung
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 41 Issue 1 Pg. 58-67 (Jan 2014) ISSN: 1872-9614 [Electronic] United States
• PMID: 24183614 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Prodrugs
• (18F)fluoroethyltyrosine
• Tyrosine
• Dipeptidases
• dipeptidase
• Amidohydrolases
• amidase

Topics

• Amidohydrolases (metabolism)
• Animals
• Biological Transport
• Brain Neoplasms (diagnostic imaging, pathology)
• Cell Line, Tumor
• Chemistry Techniques, Synthetic
• Dipeptidases (metabolism)
• Humans
• Hydrolysis
• Positron-Emission Tomography (methods)
• Prodrugs (chemical synthesis, metabolism, pharmacokinetics)
• Rats
• Tyrosine (analogs & derivatives, metabolism)