Synthesis and preliminary evaluation of 18F- or 11C-labeled bicyclic nucleoside analogues as potential probes for imaging varicella-zoster virus thymidine kinase gene expression using positron emission tomography.
Two radiolabeled bicyclic nucleoside analogues (BCNAs) were synthesized, namely 3-(2'-deoxy-beta-d-ribofuranosyl)-6-(3-[18F]fluoroethoxyphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one ([18F]-2) and 3-(2'-deoxy-beta-d-ribofuranosyl)-6-(3-[11C]methoxyphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one ([11C]-3), and evaluated as PET reporter probes for varicella-zoster virus thymidine kinase (VZV-tk) gene expression imaging in brain. [18F]-2 and [11C]-3 were synthesized starting from phenol precursor 1. The phenol precursor 1 was converted to stable as well as to radiolabeled compounds 2 and 3 using (19/18)FCH(2)CH(2)Br or (12/11)CH(3)I as alkylating agent. In vitro evaluation of [18F]-2 and [11C]-3 in 293T cells showed a 4.5 and 53-fold higher uptake, respectively, into VZV-tk gene-transduced cells compared to control cells. However, biodistribution studies in mice demonstrated low uptake of these tracers in the brain. RP-HPLC analysis of plasma and urine samples of mice injected with [11C]-3 revealed that this tracer is very stable in vivo. These data warrant further evaluation of these tracers as noninvasive imaging agents for VZV infection and VZV-tk reporter gene expression in vivo.
Chitneni
Satish K
SK
Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.
Deroose
Christophe M
CM
Balzarini
Jan
J
Gijsbers
Rik
R
Celen
Sofie J L
SJ
de Groot
Tjibbe J
TJ
Debyser
Zeger
Z
Mortelmans
Luc
L
Verbruggen
Alfons M
AM
Bormans
Guy M
GM
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology*; D002250:Carbon Radioisotopes; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D015870:Gene Expression; D014645:Herpesvirus 3, Human / Q000201:enzymology*; D006801:Humans; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000235:genetics; D014018:Tissue Distribution
C518990:3-(2'-deoxyribofuranosyl)-6-(3-fluoroethoxyphenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2-one; C518991:3-(2'-deoxyribofuranosyl)-6-(3-methoxyphenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2-one; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D011741:Pyrimidine Nucleosides; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase