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

Abstract

The specific binding and regional brain pharmacokinetics of new fluorine-18 ([(18)F])-labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-[(18)F]fluoropropyl-(+/-)-9-O-desmethyldihydrotetrabenazine ([(18)F]FP-(+/-)-DTBZ) showed better specific binding in the striatum than either (+)-[(11)C]dihydrotetrabenazine ((+)-[(11)C]DTBZ) or 9-[(18)F]fluoroethyl-(+/-)-9-O-desmethyldihydrotetrabenazine ([(18)F]FE-(+/-)-DTBZ). Using microPET, the regional brain pharmacokinetics of [(18)F]FE-(+/-)-DTBZ, [(18)F]FP-(+/-)-DTBZ and (+)-[(11)C]DTBZ were examined in the same monkey brain. (+)-[(11)C]DTBZ and [(18)F]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 [(18)F]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, [(18)F]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 [(18)F]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 [(18)F]fluoroalkyl-DTBZ ligands. The characteristics of high specific binding ratio, reversibility, metabolic stability and longer half-life of the radionuclide make [(18)F]FP-(+)-DTBZ a promising alternative VMAT2 radioligand suitable for widespread use in human positron emission tomography studies of monoaminergic innervation of the brain.

Figure 1

Structures of VMAT2 radioligands

Fig. 2

Monkey microPET images (+)-[¹¹C]dihydrotetrabenazine (DTBZ), (±)-[¹⁸F]fluoroethyldihydrotetrabenazine (FE-DTBZ), (±)-[¹⁸F]fluoropropyldihydrotetrabenazine (FP-DTBZ), and (+)-[¹⁸F]fluoropropylDTBZ. Images are transaxial slices at the level of the striatum, representing summations of the last 20 minutes of emission data (40–60 min for (+)-DTBZ, (±)-FE-DTBZ, and (±)-FP-DTBZ).

Fig. 3

Tissue time vs. radioactivity curves for striatum and cerebellum regions of interest for (+)-[¹¹C]DTBZ, [¹⁸F]FE-(±)-DTBZ, and [¹⁸F]FP-(±)-DTBZ in rhesus monkey brain (same animal for all studies).

Fig. 4

Tissue time vs. radioactivity curves for striatum, cortex, raphe, thalamus and cerebellum regions of interest for [¹⁸F]FP-(±)-DTBZ in rhesus monkey brain, with intravenous injection of 2 mg/kg tetrabenazine at 40 minutes.