In-Vivo Measurement Of Ldopa Uptake, Dopamine Reserve And Turnover In The Rat Brain Using [F-18]Fdopa Pet

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 [F-18]fluoro-3,4-dihydroxyphenyl-L-alanine ([F-18]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 [C-11]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [F-18]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [F-18]FDOPA. Effective distribution volume ratio correlated (r > 0.9) with the [C-11]DTBZ binding potential (BPND). The uptake and trapping rate (k(ref)) decreased after lesioning, but relatively less so than [C-11]DTBZ BPND. 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%. [F-18]fluoro-3,4-dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 59-66; doi: 10.1038/jcbfm.2012.120; published online 29 August 2012