Increases in striatal FDOPA influx constants in UHRP patients are not due to changes in plasma OMFD concentrations

Background: Quantification of brain PET studies with 6-[F-18]fluoro-L- DOPA(FDOPA) is complicated by its peripheral conversion by catechol-O- methyltransferase(COMT) into the metabolite 6-[F-18]fluoro-3-O-methyl-L- DOPA(OMFD) which is also transported across the blood-brain barrier. Given that genetic variation in the COMT gene may be associated with altered prefrontal cortex function and that the COMT genotypes differ in enzymatic activity[1], the present work aimed to investigate whether changes in peripheral metabolism of FDOPA could account for increases in striatal uptake in patients at ultra high risk of psychosis (UHRP) [2], who have a 20-40% chance of developing a psychotic illness in the next year[3]. Methods: Four healthy subjects (21-31years) and nine patients (20-35years) meeting UHRP criteria[3] underwent a 90-min PET scan following the injection of 150MBq of FDOPA. All subjects were pre-treated with 400mg of entacapone (peripheral COMT inhibitor) and 150mg of carbidopa (amino acid decarboxylase inhibitor) 60min prior to radiotracer injection. Discrete venous blood samples were taken for genotyping (pre-injection) and measurement of radiolabelled metabolites (at 10, 30, 60, 90min) using HPLC. The time course of the OMFD fraction in plasma was fitted to a monoexponential increase to a constant. A Patlak plot was constructed for the total striatal uptake using the cerebellar uptake as the input function and the slope (the influx constant Kic) was estimated from a linear fit of the transformed data corresponding to the time interval 20-90min. Results: The OMFD fraction in plasma at 60min was significantly higher in the UHRP patient group than in the pilot control group (0.31±0.11 vs 0.16±0.07, p<0.01). Individual measurements and fits are plotted in Fig.1 alongside the mean of those previously measured without(x, solid line) or with(+, solid line) 400mg of entacapone in six Parkinson disease patients[4] who have been found not to differ from controls[5]. Kic values significantly decreased with increasing OMFD fraction (Fig.2, R2=0.27, p<0.04) at a rate (∼10% decrease in Kic when OMFD fraction doubled) which is in accordance to prediction from simulated data[6]. Conclusion: Entacapone appears to be less effective in UHRP patients than in controls at reducing peripheral FDOPA metabolism by COMT. Higher plasma OMFD concentrations would not explain increases in Kic but instead underestimate the magnitude of real increases in striatal FDOPA uptake in URHP patients. Confirmation of these preliminary findings awaits expansion of the control group and determination of the COMT genotypes.