title: In vivo evaluation of [18F]FEAnGA-Me: a PET tracer for imaging β-glucuronidase (β-GUS) activity in a tumor/inflammation rodent model.
abstract: BACKGROUND
  The PET tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-β-d-glucopyronuronate ([(18)F]FEAnGA), was recently developed for PET imaging of extracellular β-glucuronidase (β-GUS). However, [(18)F]FEAnGA exhibited rapid renal clearance, which resulted in a relatively low tracer uptake in the tumor. To improve the pharmacokinetics of [(18)F]FEAnGA, we developed its more lipophilic methyl ester analog, [(18)F]FEAnGA-Me.
  
  
  METHODS
  [(18)F]FEAnGA-Me was obtained by alkylation of the O-protected glucuronide methyl ester precursor with [(18)F]-fluoroethylamine ([(18)F]FEA), followed by removal of the acetate protecting groups with NaOMe/MeOH. The PET tracer was evaluated by in vitro and in vivo studies.
  
  
  RESULTS
  [(18)F]FEAnGA-Me was obtained in 5%-10% overall radiochemical yield. It is 10-fold less hydrophilic than [(18)F]FEAnGA and it is stable in PBS and in the presence of β-GUS for 1 h. However, in the presence of esterase or plasma [(18)F]FEAnGA-Me is converted to [(18)F]FEAnGA, and subsequently converted to [(18)F]FEA by β-GUS. MicroPET studies in Wistar rats bearing a C6 glioma and a sterile inflammation showed similar uptake in tumors after injection of either [(18)F]FEAnGA-Me or [(18)F]FEAnGA. Both tracers had a rapid two-phase clearance of total plasma radioactivity with a half-life of 1 and 8 min. The [(18)F]FEAnGA fraction generated from [(18)F]FEAnGA-Me by in vivo hydrolysis had a circulation half-life of 1 and 11 min in plasma. Similar distribution volume in the viable part of the tumor was found after injection of either [(18)F]FEAnGA-Me or [(18)F]FEAnGA.
  
  
  CONCLUSIONS
  The imaging properties of [(18)F]FEAnGA-Me were not significantly better than those of [(18)F]FEAnGA. Therefore, other strategies should be applied in order to improve the kinetics of these tracers.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. i.farinha.antunes@umcg.nl
authors.forename: Inês F
authors.initials: IF
authors.lastname: Antunes
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.forename: Jurgen W A
authors.initials: JW
authors.lastname: Sijbesma
authors.forename: Aren van
authors.initials: Av
authors.lastname: Waarde
authors.forename: Antoon T M
authors.initials: AT
authors.lastname: Willemsen
authors.forename: Rudi A
authors.initials: RA
authors.lastname: Dierckx
authors.forename: Erik F J
authors.initials: EF
authors.lastname: de Vries
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004950:Esterases / Q000378:metabolism; D005910:Glioma / Q000000981:diagnostic imaging* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D005965:Glucuronates / Q000378:metabolism / Q000493:pharmacokinetics; D005966:Glucuronidase / Q000378:metabolism*; D006868:Hydrolysis; D007249:Inflammation / Q000000981:diagnostic imaging / Q000201:enzymology / Q000378:metabolism; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar
chemical_list: C571523:1-O-(4-(2-fluoroethylcarbamoyloxymethyl)-2-nitrophenyl)-O-glucopyronuronate; D005965:Glucuronates; D011849:Radioactive Tracers; C576455:methyl 1-O-(4-(2-fluoroethylcarbamoyloxymethyl)-2-nitrophenyl)-O-glucopyronuronate; D004950:Esterases; D005966:Glucuronidase