Biodistribution, PET, and Radiation Dosimetry Estimates of HSV-tk Gene Expression Imaging Agent 1-(2'-Deoxy-2'-18F-Fluoro- -D-Arabinofuranosyl)-5-Iodouracil in Normal Dogs

Abstract

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-(29-deoxy-29-18 F-fluoro-b-Darabinofuranosyl)-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. Conclusion: 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.

Imaging of Cell Proliferation: Status and Prospects

“…Additional TdR analogs that are resistant to catabolism and that have shown promise as potential imaging agents for cell proliferation include 1- (96,97). A recent study with 14 C-labeled thiothymidine in mice bearing syngeneic mammary tumors showed high uptake in the spleen and duodenum and moderate uptake in tumors (98).…”

Antiretroviral Tissue Kinetics: In Vivo Imaging Using Positron Emission Tomography

“…For instance, the time-activity curves for 18 F-fluoro-deoxy-D-glucose (FDG) in humans (10) or 18 F-fluoro-D-arabinofuranosyl (FIAU) in dogs (34) show evidence of peak activity within the first 10 to 20 min after radiolabel injection, followed by rapid clearance, similar to what is observed in the blood compartment. PET image kinetics confirmed the accumulation of tenofovir in the kidney, with plateau kinetics, and revealed that such accumulation is confined within the cortex (Fig.…”

PET and SPECT Reporter Gene Imaging

“…2). [13][14][16][17][18][19][20][22][23][24][25][26][27][32][33][34][35][36][37][38][39] These probes take advantage of the fact that HSV1-TK and its mutants, especially HSV1-sr39TK, have a much higher affinity for them than the cytoplasmic mammalian TKs. Amongst acycloguanosine probes, 9-(4- 18 [4][5]11,27,[34][35][36]72,[85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101] Regardless of sensitivity, the use of each probe has its advantages and disadvantages.…”