Imaging of HSV-tk Reporter gene expression: comparison between [18F]FEAU, [18F]FFEAU, and other imaging probes.
Herpes virus type 1 thymidine kinase (HSV1-tk) and the mutant HSV1-sr39tk are the 2 most widely used "reporter genes" for radiotracer-based imaging. Two pyrimidine nucleoside analogs, [18F]FEAU (1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-ethyluridine) and [18F]FFEAU (1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-(2-fluoroethyl)uridine), have generated recent interest as potential new probes for imaging HSV1-tk and HSV1-sr39tk gene expression.


METHODS
We compared [18F]FEAU and [18F]FFEAU with a series of other pyrimidine nucleoside derivatives (including 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)-5-iodouridine [FIAU]) and with acycloguanosine analogs using a stable HSV1-tk transduced cell line (RG2TK+) and wild-type RG2 cells.


RESULTS
The in vitro accumulation data and the calculated and normalized clearance constant, nKi, as well as sensitivity and selectivity indices indicated that 2 pyrimidine nucleoside probes, [18F]FEAU and [18F]FFEAU, had the best uptake characteristics. These probes were selected for further dynamic PET studies in nude rats bearing subcutaneous RG2TK+ and RG2 tumors. The 2-h postinjection [18F]FEAU uptake levels were 3.3% +/- 1.0% and 0.28% +/- 0.07% dose/cm3 in subcutaneous RG2TK+ and RG2 tumors, respectively, and 2.3% +/- 0.2% and 0.19% +/- 0.01% dose/cm3, respectively, for [18F]FFEAU. The corresponding RG2TK+/RG2 uptake ratios were 11.5 +/- 1.5 and 12.2 +/- 1.4, respectively. The inherent problem of comparing different radiolabeled pyrimidine nucleoside and guanosine-based probes for imaging HSV1-tk expression using different transduced cell lines and assay systems in the absence of an independent thymidine kinase-enzyme assay is discussed.


CONCLUSIONS
For HSV1-tk reporter systems that require a 1- to 4-h PET paradigm, HSV1-tk-[18F]FEAU is the current top contender.
Miyagawa
Tadashi
T
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Gogiberidze
George
G
Serganova
Inna
I
Cai
Shangde
S
Balatoni
Julius A
JA
Thaler
Howard T
HT
Ageyeva
Lyudmila
L
Pillarsetty
Nagavarakishore
N
Finn
Ronald D
RD
Blasberg
Ronald G
RG
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D017930:Genes, Reporter; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D019275:Radiopharmaceuticals; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics*
C508411:2'-fluoro-2'-deoxy-5-fluoroethyl-1-beta-D-arabinofuranosyl uracil; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D001086:Arabinofuranosyluracil; C054103:2'-fluoro-5-ethylarabinosyluracil; D013937:Thymidine Kinase