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Synthesis of [⁷⁶Br]Bromofluorodeoxyuridine and Its Validation with Regard to Uptake, DNA Incorporation, and Excretion Modulation in Rats

PET Center, Uppsala University Hospital, Uppsala; and Department of Pharmaceutics, Uppsala University, Uppsala, Sweden

This investigation aimed to validate 5-[⁷⁶Br]bromo-2'-fluoro-2'-deoxyuridine (BFU) as a proliferation marker using PET. Methods: Five megabecquerels ⁷⁶Br-BFU were injected into the tail vein of Sprague-Dawley rats. At 6 or 16 h after injection, the rats were killed and the radioactivity concentration was measured in 6 different organs and blood. The fraction of radioactivity incorporated into DNA was determined for the spleen and small intestine. In parallel experiments, the animals were pretreated with hydroxyurea. In a few experiments, the urinary excretion of radioactivity was measured from administration of ⁷⁶Br-BFU until 6 h. A sample of urine was analyzed with HPLC. In separate experiments, rats were given different doses of cimetidine, and the organ uptake and the fraction of radioactivity in DNA were determined at 24 h. Results: The highest organ uptake of radioactivity was found in the spleen, followed by the small intestine. Approximately 90% of the radioactivity in these organs was incorporated into DNA, and inhibition by hydroxyurea was pronounced. Intact tracer constituted more than 95% of the radioactivity in urine. With cimetidine, the uptake of radioactivity increased approximately 2–5 times at different doses, whereas the urine radioactivity decreased markedly. Conclusion: ⁷⁶Br-BFU was predominantly incorporated into DNA after administration in vivo in rats. If cimetidine was given in combination with the tracer, an increased contrast of radioactivity concentration between organs of high proliferation and organs of low proliferation was observed. The investigation suggested that ⁷⁶Br-BFU has good potential as a PET tracer for the assessment of proliferation in vivo.

Key Words: PET • bromodeoxyuridine • DNA synthesis • hydroxyurea • cimetidine

Received Nov. 5, 1999; revision accepted Mar. 28, 2000.

For correspondence or reprints contact: Mats Bergström, PhD, PET Center, Uppsala University Hospital, 751 85 Uppsala, Sweden.

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