meta-[18F]Fluorobenzylguanidine ([18F]MFBG) and para-[18F]fluorobenzylguanidine ([18F]PFBG) were synthesized in three steps beginning with a fluoro for nitro exchange reaction on 3- and 4-nitrobenzonitrile, respectively. Overall radiochemical yields were 10-15% for [18F]MFBG and 50-55% for [18F]PFBG in a total synthesis time of 60 min. However, impurities interfered with the binding of the product to target cells. A new route was adopted for the synthesis of [18F]PFBG using 4-nitrilophenyl trimethylammonium trifluoromethanesulfonate (Q.S.) as the starting material. In addition to shortening the overall synthesis time by 10 min, this precursor also eliminated problems associated with the presence of small amounts of starting material in the preparation. In vitro binding of [18F]PFBG prepared by the Q.S. method to SK-N-SH, human neuroblastoma cells was 26.5 +/- 1.1%, compared to 16.9 +/- 1.6% when the nitro precursor was used. Selective uptake of both 18F-labeled isomers in the heart and adrenal was seen in mice. At 4 h, adrenal and heart uptake of [18F]PFBG prepared using Q.S. was 20.3 +/- 4.8 and 5.9 +/- 0.8% ID/g respectively, compared to 23.8 +/- 5.0 and 10.5 +/- 1.7% ID/g for [18F]MFBG. Based on the 5-fold higher radiochemical yields obtained with [18F]PFBG, this isomer would appear to be the more practical choice; however, in vitro and in vivo results suggest that [18F]MFBG exhibits greater similarities to MIBG.