title: In-vivo measurement of LDOPA uptake, dopamine reserve and turnover in the rat brain using [18F]FDOPA PET.
abstract: Longitudinal measurements of dopamine (DA) uptake and turnover in transgenic rodents may be critical when developing disease-modifying therapies for Parkinson's disease (PD). We demonstrate methodology for such measurements using [(18)F]fluoro-3,4-dihydroxyphenyl-L-alanine ([(18)F]FDOPA) positron emission tomography (PET). The method was applied to 6-hydroxydopamine lesioned rats, providing the first PET-derived estimates of DA turnover for this species. Control (n=4) and unilaterally lesioned (n=11) rats were imaged multiple times. Kinetic modeling was performed using extended Patlak, incorporating a k(loss) term for metabolite washout, and modified Logan methods. Dopaminergic terminal loss was measured via [(11)C]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [(18)F]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [(18)F]FDOPA. Effective distribution volume ratio correlated (r>0.9) with the [(11)C]DTBZ binding potential (BP(ND)). The uptake and trapping rate (k(ref)) decreased after lesioning, but relatively less so than [(11)C]DTBZ BP(ND). For normal controls, striatal estimates were k(ref)=0.037±0.005 per minute, EDVR=1.07±0.22 and k(loss)=0.024±0.003 per minute (30 minutes turnover half-time), with repeatability (coefficient of variation) ≤11%. [(18)F]fluoro-3,4-dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD.
authors.affiliation: Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada. mwalker@physics.ubc.ca
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Walker
authors.forename: Katherine
authors.initials: K
authors.lastname: Dinelle
authors.forename: Rick
authors.initials: R
authors.lastname: Kornelsen
authors.forename: Siobhan
authors.initials: S
authors.lastname: McCormick
authors.forename: Chenoa
authors.initials: C
authors.lastname: Mah
authors.forename: James E
authors.initials: JE
authors.lastname: Holden
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
authors.forename: Vesna
authors.initials: V
authors.lastname: Sossi
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D005462:Fluorine Radioisotopes; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D016627:Oxidopamine; D004298:Dopamine