In vivo evaluation of [F-18]FEAnGA-Me: a PET tracer for imaging beta-glucuronidase (beta-GUS) activity in a tumor/inflammation rodent model

摘要

Introduction: The PET tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-beta-D-glucopyronuronate ([F-18]FEAnGA), was recently developed for PET imaging of extracellularl beta-glucuronidase (beta-GUS). However,[F-18]FEAnGA exhibited rapid renal clearance, which resulted in a relatively low tracer uptake in the tumor. To improve the pharmacokinetics of [F-18]FEAnGA, we developed its more lipophilic methyl ester analog, [F-18]FEAnGA-Me. Methods: [F-18]FEAnGA-Me was obtained by alkylation of the O-protected glucuronide methyl ester precursor with [F-18]-fluoroethylamine ([F-18]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: [F-18]FEAnGA-Me was obtained in 5%-10% overall radiochemical yield. It is 10-fold less hydrophilic than [F-18]FEAnGA and it is stable in PBS and in the presence of beta-GUS for 1 h. However, in the presence of esterase or plasma [F-18]FEAnGA-Me is converted to [F-18]FEAnGA, and subsequently converted to [F-18]FEA by beta-GUS. MicroPET studies in Wistar rats bearing a C6 glioma and a sterile inflammation showed similar uptake in tumors after injection of either [F-18]FEAnGA-Me or [F-18]FEAnGA. Both tracers had a rapid two-phase clearance of total plasma radioactivity with a half-life of 1 and 8 min. The [F-18]FEAnGA fraction generated from [F-18]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 [F-18]FEAnGA-Me or [F-18]FEAnGA. Conclusion: The imaging properties of [F-18]FEAnGA-Me were not significantly better than those of [F-18]FEAnGA. Therefore, other strategies should be applied in order to improve the kinetics of these tracers. (C) 2012 Elsevier Inc. All rights reserved.