Imaging of vesicular monoamine transporter 2 (VMAT2) in the brain with [(11)C]-dihydrotetrabenazine (DTBZ) in conjunction with positron emission tomography (PET) has demonstrated its usefulness in the diagnosis and monitoring of neurodegenerative diseases such as Parkinson's disease and Huntington's disease. We report on the development of (18)F analogs of DTBZ with a longer half-life (t=110 vs. 20 min for C-11) to increase the availability of VMAT2 imaging agents for routine clinical studies with PET. Racemic 9-fluoroethyl (FE) and 9-fluoropropyl (FP)-9-desmethyl-DTBZ and the corresponding hydroxyl derivatives were successfully prepared. No-carrier-added racemic (18)F-DTBZ derivatives were synthesized by an [(18)F]fluoride displacement of the corresponding mesylates with good yields (30-40%) and high specific activity (SA=1500-2000 Ci/mmol). Racemic (+/-)-FE-DTBZ (6a) and (+/-)-FP-DTBZ (6b) displayed excellent binding affinities (K(i)=0.76 and 0.56 nM, respectively) for VMAT2 binding sites in rat striatal homogenates, whereas the known compounds (+/-)-DTBZ and (+/-)-tetrabenazine (TBZ) showed K(i) values of 1.7+/-0.2 and 1.3+/-0.1 nM, respectively. Consistently, racemic [(18)F]6a and [(18)F]6b exhibited K(d) values of 0.52 and 0.48 nM, respectively (based on an SA of 2000 Ci/mmol), for VMAT2 binding sites using mouse striatal homogenates. Both agents showed comparable binding densities with those obtained with [(3)H](+/-)-TBZ. Results of in vitro autoradiography with [(18)F]6b showed a distinct binding in the caudate putamen region consistent with the localization of VMAT2 in the mouse brain, which was blocked by nonradioactive TBZ efficiently. Biodistribution studies on mice after an intravenous injection of the tracer exhibited excellent brain uptakes (4.66% and 7.08% ID/g at 2 min for racemic [(18)F]6a and [(18)F]6b, respectively). It was determined that [(18)F]6b displayed a faster brain washout than [(18)F]6a did. As a result, [(18)F]6b yielded a better target-to-background ratio (striatum/cerebellum=3.0 and 1.7 at 30 min after an intravenous injection for [(18)F]6b and [(18)F]6a, respectively). The blocking study with the nonradioactive (+/-)-DTBZ clearly confirmed the in vivo competition and specificity of [(18)F]6b binding for VMAT2 sites. In conclusion, these findings strongly suggest that the novel racemic [(18)F]6b is potentially useful as a molecular imaging agent for VMAT2 binding sites in the brain. Further studies are warranted to assess the utility of these (18)F-labeled DTBZ derivatives as PET tracers for the diagnosis of various neurodegenerative diseases.