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Rat Studies Comparing ¹¹C-FMAU, ¹⁸F-FLT, and ⁷⁶Br-BFU as Proliferation Markers

¹ PET Center, Uppsala University Hospital, Uppsala, Sweden
² Department of Pharmaceutics, Uppsala University, Uppsala, Sweden
³ Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Uppsala, Sweden
⁴ Hamamatsu Photonics, Shizuoka, Japan

We analyzed and compared 1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl)-[methyl-¹¹C]thymine (¹¹C-FMAU), 3'-deoxy-3'-[¹⁸F]fluorothymidine (¹⁸F-FLT) and 1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl)-5-[⁷⁶Br]bromouracil (⁷⁶Br-BFU) with respect to tissue uptake, DNA incorporation, and excretion modulation in rats. The goal of the investigation was to evaluate the efficiency of the 3 nucleoside tracers as potential tracers for measuring proliferation. Methods: Sprague-Dawley rats were divided into 3 groups and administered 5 MBq ¹¹C-FMAU, 1 MBq ¹⁸F-FLT, or 2 MBq ⁷⁶Br-BFU. For each tracer, a subgroup was also administered 6 mg/kg cimetidine. The rats in the ¹¹C-FMAU group were killed at 5, 20, 40, 60, and 80 min after injection; the rats in the ¹⁸F-FLT group were killed at 80 min and 2 and 4 h; and the rats in the ⁷⁶Br-BFU group were killed at 5, 20, 40, and 80 min and 2, 4, 6, and 24 h. Samples of blood, liver, kidney, spleen, and intestine were taken, and the radioactivity was measured. DNA separation was made in the samples of spleen, and the radioactivity in the DNA fraction was measured. Results: Maximal uptake of radioactivity was seen in the spleen and intestine, organs with active DNA synthesis. The highest relative radioactivity uptake was at 60 min in the ¹¹C-FMAU groups and at 4 h in the ¹⁸F-FLT group. In the ⁷⁶Br-BFU group, the uptake increased gradually during the observation period, and uptake of radioactivity increased markedly in rats receiving cimetidine. Cimetidine did not affect radioactivity uptake in the ¹¹C-FMAU or ¹⁸F-FLT groups. The fraction of radioactivity in DNA was 78% in spleen at 60 min in the ¹¹C-FMAU group, 80% at 60 min and 97% at 4 h in the ⁷⁶Br-BFU group. The DNA-incorporation was only 2% in the ¹⁸F-FLT group. Conclusion: ⁷⁶Br-BFU predominantly incorporates into DNA and has great potential as a PET tracer for the assessment of proliferation in vivo. ¹¹C-FMAU also may have potential as a proliferation marker, but the observation time is limited. ¹⁸F-FLT does not incorporate into DNA and is therefore not a direct marker of proliferation.

Key Words: PET • ¹¹C-FMAU • ¹⁸F-FLT • ⁷⁶Br-BFU • DNA synthesis