Pharmacokinetics of [18F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain

The specific binding and regional brain pharmacokinetics of new fluorine-18 ([18F])-labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-[18F]fluoropropyl-(±)-9-O-desmethyldihydrotetrabenazine ([18F]FP-(±)-DTBZ) showed better specific binding in the striatum than either (+)-[11C]dihydrotetrabenazine ((+)-[11C]DTBZ) or 9-[18F]fluoroethyl-(±)-9-O-desmethyldihydrotetrabenazine ([18F]FE-(±)-DTBZ). Using microPET, the regional brain pharmacokinetics of [18F]FE-(±)-DTBZ, [18F]FP-(±)-DTBZ and (+)-[11C]DTBZ were examined in the same monkey brain. (+)-[11C]DTBZ and [18F]FP-(±)-DTBZ showed similar brain uptakes and pharmacokinetics, with similar maximum striatum-to-cerebellum ratios (STR/CBL=5.24 and 5.15, respectively) that were significantly better than obtained for [18F]FE-(±)-DTBZ (STR/CBL=2.55). Striatal distribution volume ratios calculated using Logan plot analysis confirmed the better specific binding for the fluoropropyl compound [distribution volume ratio (DVR)=3.32] vs. the fluoroethyl compound (DVR=2.37). Using the resolved single active isomer of the fluoropropyl compound, [18F]FP-(+)-DTBZ, even better specific to nonspecific distribution was obtained, yielding the highest distribution volume ratio (DVR=6.2) yet obtained for a VMAT2 ligand in any species. The binding of [18F]FP-(+)-DTBZ to the VMAT2 was shown to be reversible by administration of a competing dose of unlabeled tetrabenazine. Metabolic defluorination was slow and minor for the [18F]fluoroalkyl-DTBZ ligands. The characteristics of high specific binding ratio, reversibility, metabolic stability and longer half-life of the radionuclide make [18F]FP-(+)-DTBZ a promising alternative VMAT2 radioligand suitable for widespread use in human positron emission tomography studies of monoaminergic innervation of the brain.