The synthesis of 4-[18F]fluoroantipyrine (1) and its biodistribution in mice are described. Compound 1 was synthesized either by direct fluorination of antipyrine with [18F]F2 or CH3CO2 18F, or by an isotopic exchange method. While direct fluorination of antipyrine with [18F]F2 gave compound 1 in about a 20% yield, the isotopic exchange method gave compound 1 in only a 1%-2% yield. The biodistributions of compound 1 and 4-[131I]iodoantipyrine (3) in mice indicated that both compounds reached apparent equilibrium concentration in the bloodstream at approximately 0.5 min postinjection and compound 1 was found in higher concentrations than the iodinated analog in the well-perfused tissues. The 18F activity in the mouse brain persisted for about 2 min. The ratio of activity in the brain to bone was approximately 2:1. After 10 min, the 18F activity in the brain decreased markedly while the 18F activity in bones rose sharply resulting in a brain to bone ratio of approximately 1:2. This would suggest that compound 1 defluorinated in vivo to give fluoride as one of the metabolites. The mean octanol/pH 7 buffer solution partition coefficients of 4-[18F]fluoroantipyrine and 4-[131I]iodoantipyrine were 5.18 +/- 0.10 and 11.34 +/- 0.28, respectively.