Biodistribution, PET, and radiation dosimetry estimates of HSV-tk gene expression imaging agent 1-(2'-Deoxy-2'-18F-Fluoro-beta-D-arabinofuranosyl)-5-iodouracil in normal dogs.
FIAU is of interest as a potential reporter probe to monitor herpes simplex virus thymidine kinase (HSV-tk) gene expression and bacterial infections. This study investigates the biodistribution, metabolism, and DNA uptake of 1-(2'-deoxy-2'-(18)F-fluoro-beta-d-arabinofuranosyl)-5-iodouracil ((18)F-FIAU) in normal dogs.


METHODS
Four normal dogs were intravenously administered (18)F-FIAU. A dynamic PET scan was performed for 60 min over the upper abdomen; this was followed by a whole-body scan for a total of 150 min on 3 dogs. The fourth dog was not scanned and was euthanized at 60 min. Blood and urine samples were collected at stipulated time intervals and analyzed by high-performance liquid chromatography to evaluate tracer clearance and metabolism. Tissue samples collected from various organs were analyzed to evaluate tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. Nondecay-corrected time-activity curves were used for residence time calculation and absorbed dose estimation.


RESULTS
At 60 min after injection, unmetabolized FIAU radioactivity in blood and urine samples was greater than 78% and 63%, respectively, demonstrating resistance to metabolism. The tissue-to-muscle ratio derived from image and tissue analysis showed a slightly higher uptake in proliferating organs (mean tissue-to-muscle values: small intestine, 1.97; marrow, 1.70) compared with nonproliferative organs (heart, 1.07; lung, 1.06). A high concentration of activity was seen in the bile (mean, 23.02), demonstrating hepatobiliary excretion of the tracer. Extraction analysis of tissue samples showed that >62% of the activity in the small intestine, 74% in marrow, and <21% in heart, liver, and muscle was incorporated into DNA.


CONCLUSIONS
These results demonstrate that FIAU is resistant to metabolism and moderately incorporates into DNA in proliferating tissues. These results suggest that incorporation into the DNA of normal tissues may need to be considered when FIAU is used to track reporter gene activity. Studies in humans are needed to determine whether imaging properties differ in patients and are altered as a result of metabolism changes affected by gene therapies.
Nimmagadda
Sridhar
S
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201-2013, USA.
Mangner
Thomas J
TJ
Douglas
Kirk A
KA
Muzik
Otto
O
Shields
Anthony F
AF
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004247:DNA / Q000378:metabolism; D004285:Dogs; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011874:Radiometry / Q000379:methods*; D018139:Simplexvirus / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics*; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D001086:Arabinofuranosyluracil; C043457:fialuridine; D004247:DNA; D013937:Thymidine Kinase