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.