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Basic Science Investigations |
1 Department of Medicine, Wayne State University, Detroit, Michigan
2 Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
3 Department of Radiology, Wayne State University, Detroit, Michigan
4 Food and Drug Administration, Rockville, Maryland
5 Department of Pediatrics, Wayne State University, Detroit, Michigan
We imaged DNA synthesis in vivo with PET and 18F-1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl)thymine (FMAU), which is phosphorylated by thymidine kinases and incorporated into DNA. Methods: We produced 18F-FMAU and injected the tracer into 5 normal dogs and studied them by imaging or biodistribution for up to 2.5 h. The pharmacokinetics of FMAU in blood and urine were determined using high-performance liquid chromatography analysis. At the end of each study, selected tissues were removed to measure the total activity retained in these tissues. In addition, the selected tissues were extracted by acid precipitation, by which the macromolecules can be precipitated to determine the radioactivity of 18F-FMAU incorporated into DNA. Results: Imaging and tissue analysis showed increased activity in the lymph nodes, stomach, small intestine, and bone marrow, with mean standardized uptake values of 1.4, 1.6, 2.3, and 3.9, respectively, because of varying degrees of increased cell proliferation. In contrast, 18F-FMAU was distributed with tissue-to-muscle ratios of approximately 1.0 in nonproliferative organs such as lung, liver, and kidneys. Analysis of the tissue extracts using acid precipitation demonstrated that 88% of activity in marrow and 65% of activity in small intestine was acid precipitated. However, more than 90% of activity in the nonproliferating tissues such as heart and lungs was in the supernatant. Increased activity was seen in the heart because of a high level of thymidine kinase 2 and in the gallbladder because of excretion. Analysis of blood and urine demonstrated that more than 95% of activity was present as intact 18F-FMAU at the end of the studies. Conclusion: The results showed that 18F-FMAU was selectively retained in DNA of the proliferating tissues and was resistant to degradation. These features indicate that 18F-FMAU might be an alternative to 11C-thymidine for imaging DNA synthesis in normal tissues and tumors.
Key Words: FMAU • PET • proliferation
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