[18F]FBAU 3',5'-dibenzoate, a lipophilic prodrug, enhances brain uptake of the cell proliferation tracer [18F]FBAU.
BACKGROUND
1-(2-deoxy-2-[(18)F]fluoro-beta-D-arabinofuranosyl)-5-bromouracil ([(18)F]FBAU) is a cell proliferation tracer. However, it does not pass readily through the blood-brain barrier. We synthesized a lipophilic prodrug of [(18)F]FBAU that was intended to enhance brain uptake of [(18)F]FBAU to improve the imaging of brain cell proliferation.


METHODS
[(18)F]FBAU was synthesized according to the methods described by Alauddin [J Med Chem 39 (1996) 2835-2843]. The prodrug, 1-(2-deoxy-3,5-O-dibenzoyl-2-[(18)F]fluoro-beta-D-arabinofuranosyl)-5-bromouracil ([(18)F]FBAU 3',5'-dibenzoate), was purified from an intermediate of [(18)F]FBAU. Their lipophilicity was determined by performing octanol/water partition coefficient (log P) measurements. In vitro metabolic fates of the prodrug were examined in rat and mouse plasma and brain homogenates. Brain uptake was determined following iv injection of the radiotracers by killing animals at various time points and dissecting and counting the radioactivity accumulation in the various tissues.


RESULTS
Values of log P for [(18)F]FBAU 3',5'-dibenzoate and [(18)F]FBAU were 3.95 and -0.35, respectively. In rat plasma, the prodrug was gradually hydrolyzed to [(18)F]FBAU. Thirty minutes after mixing [(18)F]FBAU 3',5'-dibenzoate in the plasma, 25% of the prodrug had been hydrolyzed. The hydrolysis went more slowly in brain homogenates. At 15 min post injection, relative to animals injected with [(18)F]FBAU, brain uptake of radioactivity in animals injected with [(18)F]FBAU 3',5'-dibenzoate was increased by 150% (P=.005) and 78% (P=.037) in rats and mice, respectively. At 60 min post injection, the radioactive contents extracted from the brain were mostly [(18)F]FBAU.


CONCLUSIONS
The synthesized novel prodrug [(18)F]FBAU 3',5'-dibenzoate has enhanced brain uptake in rodents, suggesting it may be useful as an imaging agent for tracing brain cell proliferation.
Kao
Chih-Hao K
CH
Department of Radiopharmaceutical Production, Buddhist Tzu Chi General Hospital, Hualien, Taiwan. kevin_kao@tzuchi.com.tw
Xie
Heng-Li
HL
Liao
Chia-Hsin
CH
Chen
Wen-Min
WM
Kao
Pan-Fu
PF
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D001976:Bromouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D049109:Cell Proliferation; D002498:Centrifugation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000000981:diagnostic imaging; D007553:Isotope Labeling; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011849:Radioactive Tracers; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013154:Spleen / Q000000981:diagnostic imaging / Q000378:metabolism
C470853:1-(2-fluoro-2-deoxy-3,5-O-dibenzoylarabinofuranosyl)-5-bromouracil; C470854:1-(2-fluoro-2-deoxyarabinofuranosyl)-5-bromouracil; D008055:Lipids; D011355:Prodrugs; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; D001976:Bromouracil; D004247:DNA