title: 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.
authors: Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA. mkilbour@umich.edu
authors: Michael R
authors: MR
authors: Kilbourn
authors: Brian
authors: B
authors: Hockley
authors: Lihsueh
authors: L
authors: Lee
authors: Catherine
authors: C
authors: Hou
authors: Rajesh
authors: R
authors: Goswami
authors: Datta E
authors: DE
authors: Ponde
authors: Mei-Ping
authors: MP
authors: Kung
authors: Hank F
authors: HF
authors: Kung
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D000882:Haplorhini; D008657:Metabolic Clearance Rate; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D013747:Tetrabenazine