1-(2'-Deoxy-2'-[ 18 F]fluoro-β- d-arabinofuranosyl)-5-iodocytosine

Liang Shan

PMID: 22514809

Abstract:

The 18F-labeled 1-(2'-deoxy-2'-[18F]fluoro-β-d-arabinofuranosyl)-5-iodocytosine, abbreviated as 18F-FIAC, is a cytidine analog synthesized for positron emission tomography (PET) of herpes simplex virus (HSV) type 1 thymidine kinase (HSV1-tk) gene expression (1, 3).
The HSV1-tk reporter gene expression was first explored with radiolabeled nucleoside analogs by Tjuvajev et al. in 1995 to monitor the activity of HSV1-tk (4). This study opened a new field of imaging of HSV1-tk gene expression in gene therapy of cancer (2, 5). Since then, a large number of radiolabeled nucleoside analogs have been reported for PET imaging of HSV1-tk reporter gene expression (2, 3). These analogs have been developed on the basis of their antiviral properties against HSV for treatment of HSV encephalitis, which involves monophosphorylation of the nucleoside analogs by HSV1-tk to their monophosphates that are subsequently converted to their di- and tri-phosphates by host kinases (1). Basically, these analogs can be divided into two major classes: pyrimidine and purine nucleoside analogs (2). The pyrimidine analogs are 2'-18F-fluoroarabinofuranisyluracil derivatives and a few other 5- and 6-substituted uracil derivatives. The purine analogs are fluorinated guanosine (acycloguanosine) derivatives. Pyrimidine analogs have two advantages over the guanosine analogs. First, pyrimidine nucleosides are more sensitive (by orders of magnitude) to HSV1-tk than guanosine nucleosides. Second, pyrimidine analogs are mainly cleared via the kidneys; therefore, the background activity is negligible, whereas most guanosine nucleosides are cleared through the hepatobiliary system, which leads to high radioactivity in the intestine. However, pyrimidine analogs are substrates of thymidine phosphorylase (TPase), and the glycosilic bond between the sugar and the base in the structure can be cleaved by TPase, whereas guanosine analogs are resistant to TPase; therefore, guanosine nucleosides often exhibit better tracer kinetics in this respect than the pyrimidine nucleosides. In addition, because guanosine nucleosides are not TPase substrates, they are more attractive for PET imaging of mutated HSV1-tk reporter gene expression (6).
FIAC is a potent inhibitor of HSV virus replication. In virus-infected cells, FIAC is transformed to mono-, di-, or tri-phosphate form and incorporated into the viral DNA sequence to cause anti-viral effects at concentrations as low as 10 nM (7, 8). At the same time, FIAC exhibits limited cytotoxicity (IC50 = 21.7 μM) to untransfected cells, indicating that FIAC might not be a proper substrate for the host thymidine kinase (8). These findings imply that FIAC might be an ideal probe for targeting HSV1-tk gene expression in living subjects. Chan et al. (1) tested the feasibility of 18F-FIAC as a PET radiotracer for HSV1-tk gene imaging and compared it with two highly promising thymidine analogs, 2'-deoxy-2'-[18F]fluoro-5-iodo-1-β-d-arabinofuranosyluracil (18F-FIAU) and 2'-deoxy-2'-[18F]fluoro-5-ethyl-1-β-d-arabinofuranosyluracil (18F-FEAU) (9) in an NG4TL4-WT/STK sarcoma-bearing mouse model. This chapter summarizes the data obtained with 18F-FIAC.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP59277893-A	Acycloguanosine		59277-89-3	Price