Cerebral 6-[18F]fluoro-L-DOPA (FDOPA) metabolism in pig studied by positron emission tomography

Abstract

We measured 6-[(18)F]fluoro-L-DOPA (FDOPA) uptake and metabolism in the brain of 4-month-old female pigs (n = 8) using a high-resolution positron emission tomograph (PET) in 3D mode. The mean net blood-brain clearance of FDOPA (K(i)(D)) to striatum was 0.011 ml g(-1) min(-1). Correcting for the elimination of decarboxylated metabolites from striatum (k(loss) = 0.004 min(-1)) increased the apparent magnitude of the estimate of K(i)(D) by 50%, at the expense of doubling the variance of the mean estimate. The mean decarboxylation rate of FDOPA in striatum relative to the cerebellum input (k(3)(s)) was 0.008 min(-1). For multicompartmental analyses, the FDOPA partition volume (V(e)(D)) was constrained to the individual value observed in cerebellum (mean = 0.53 ml g(-1)), with correction for the presence in brain of the plasma metabolite 3-O-methyl-FDOPA (OMFD). Using the first 60 min of the dynamic PET scans, the rate constant of FDOPA decarboxylation (k(3)(D)) was estimated to be 0.037 min(-1 )in striatum, but was not significantly different than zero in frontal cortex. Fitting of a compartmental model correcting for elimination of decarboxylated metabolites to the complete PET frame-sequence (120 min) increased the variance of the estimate of k(3)(D) in striatum. The magnitude of k(3)(D) in striatum of young pig was less than values estimated previously in neonatal piglet, adult monkey, and human. MRI-based simulations predicted that recovery of radioactivity from pig striatum was highly sensitive to the volume of interest. We conclude that the spatial resolution of our tomograph reduces the apparent magnitude of k(3)(D) in striatum. However, anaesthetised pigs are an appropriate experimental model for PET studies of DOPA decarboxylation in striatum.

The use of pigs in neuroscience: Modeling brain disorders

“…PET recordings of the cerebral uptake of the exogenous substrate [ 18 F]fluoro-L-DOPA (FDOPA) can be used as an assay for DOPA decarboxylase activity in nigrostriatal dopamine terminals. Kinetics for the cerebral metabolism of FDOPA in living pig resembles closely earlier findings in rat, monkey and human with this widely used PET tracer (Danielsen et al, 1999). Optimal methods for quantification of FDOPA uptake have been established in pig brain , and using FDOPA/PET, developmental changes in the influx of large neutral amino acids (Brust et al, 2004a), DOPA decarboxylase activity (Brust et al, 2004b), and vulnerability of dopamine systems of traumatic brain injury (Walter et al, 2004) have been assessed in neonate and young adult pigs.…”

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

“…A reversible trapping model for FDOPA was first introduced in 1991 (Huang et al, 1991) but suffered from instability when only 2-h FDOPA emission recordings were available (Danielsen et al, 1999). A modified graphical method with a correction term for loss of decarboxylated metabolites was introduced for the analysis of FDOPA/PET studies (Holden et al, 1997;Sossi et al, 2001).…”

“…Early attempts to estimate FDOPA steady-state kinetics during 120 min recordings failed to yield stable parameter esti-mates (Danielsen et al, 1999). Consequently, we recently developed advanced methods for calculating the intrinsic unidirectional clearance of FDOPA to brain (K, ml ⅐ g Ϫ1 ⅐ min Ϫ1 ), the fractional rate constant for elimination of [ 18 F]fluorodopamine and its metabolites from brain (k loss ) (min Ϫ1 ), and the steadystate distribution volume of the total radioactive tracer concentration in brain (V d , ml/g) , using time-activity curves of only 120 min duration.…”

MRI-guided stereotaxic targeting in pigs based on a stereotaxic localizer box fitted with an isocentric frame and use of SurgiPlan computer-planning software

“…Furthermore, the use of pigs for research seems to be more acceptable than primate research, which lately has been the focus of increased public debate resulting in life-threatening attacks on primate researchers by extreme animal rights activists (Goodman and Check, 2002;Krystal et al, 2008). The pig is well suited for brain research as its large gyrated brain allows imaging with conventional CT, MRI, and PET-scanners and neurosurgical approaches based on the use or testing of instrumentation developed for human (clinical) use (Danielsen et al, 1998(Danielsen et al, , 1999Roberts et al, 1999;Sakoh et al, 2000Sakoh et al, , 2001Tacke et al, 2001;Erikson et al, 2002;Platenik et al, 2002;Rohl et al, 2002;Dalmose et al, 2004;Bjarkam et al, 2005Bjarkam et al, , 2008Manley et al, 2006;Lind et al, 2007). Young animals from conventional pig breeds such as Landrace, Duroc and Yorkshire may, accordingly, be well suited for such studies.…”

“…We have used this animal for studies on intracerebral implantation of fetal dopaminergic tissue, and deep brain stimulation (DBS) electrodes for the treatment of Parkinson disease and supraspinal 0165-0270/$ -see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jneumeth.2009.06.019 neurogenic voiding disorders (Danielsen et al, 1998(Danielsen et al, , 1999Mikkelsen et al, 1999;Cumming et al, 2001;Dalmose et al, 2004;Bjarkam et al, 2005Bjarkam et al, , 2008Jensen et al, 2009). However, both the mentioned minipig breeds and the larger domestic pig breeds develop post-puberty e.g.…”