A new cardiac sympathetic nerve imaging agent, [ 18 F]4-fluoro-m-hydroxyphenethylguanidine ([ 18 F]4F-MHPG), was synthesized and evaluated. The radiosynthetic intermediate [ 18 F]4-fluoro-m-tyramine ([ 18 F]4F-MTA) was prepared and then sequentially reacted with cyanogen bromide and NH 4 Br/NH 4 OH to afford [ 18 F]4F-MHPG. Initial bioevaluations of [ 18 F]4F-MHPG (biodistribution studies in rats and kinetic studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled analog [ 11 C]4F-MHPG. The neuronal uptake rate of [ 18 F]4F-MHPG into the isolated rat heart was 0.68ml/min/g wet and its retention time in sympathetic neurons was very long (T 1/2 >13h). A PET imaging study in a nonhuman primate with [ 18 F]4F-MHPG provided high quality images of the heart, with heart-to-blood ratios at 80–90min after injection of 5-to-1. These initial kinetic and imaging studies of [ 18 F]4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional cardiac sympathetic nerve density than is currently possible with existing neuronal imaging agents.