The Distribution and Kinetics of [¹⁸F]6-Fluoro-3-O-Methyl-l-Dopa in the Human Brain

Abstract

Summary: The analysis of positron tomographic studies of 3,4-dihydroxyphenylethylamine (dopamine) metabo lism in which e8F]6-fluoro-L-3,4-dihydroxyphenylalanine (F-dopa) is used as a tracer is confounded by the presence of [18Fj6-fluoro-3-0-methyl-L-3,4-dihydroxyphenylala nine (OMFD). This labeled molecule, formed by the ac tion of peripheral cathechol-O-methyltransferase on F-dopa, crosses the blood-brain barrier and contributes to the radioactivity measured by the tomograph. Correc tions for this radioactivity in the brain have been pro posed. They rely upon the assumption that regional vari ations in the handling of this molecule by the brain are negligible. Although this assumption is pivotal for the proper quantification of dopamine metabolism using F-dopa, the distribution and kinetics of OMFD have never been studied in humans. We present results in hu mans that show that there is little selective regional 18F accumulation in the brain, that the distribution volume of Positron tomography used with a labeled precur sor of 3,4-dihydroxyphenylethylamine (dopamine) offers the best approach to the investigation of pre synaptic dopamine metabolism in living humans. The most commonly used tracer is an analogue of L-3,4-dihydroxyphenylalanine (L-dopa) labeled with fluorine-I 8: [ l sF16-fluoro-L-dopa (F -dopa). How ever, the analysis of the data has been confounded by the presence of other labeled species formed in the body, which cross the blood-brain barrier. Like L-dopa, F-dopa acts as a substrate for catechol-OReceived June 9, 1993; final revision received December 9, 1993; accepted January 12, 1994. 664OMFD is close to unity, and that a single, reversible com partment is adequate to model the measured time course of radioactivity after an OMFD injection. Analysis of plasma samples for labeled metabolites showed that more than 95% of the radioactivity was associated with OMFD at all times. Our results for OMFD kinetics are in accord with published results obtained in nonhuman primates and for the bidirectional transport of large neutral amino acids across the blood-brain barrier measured using a synthetic amino acid. However, our results also indicate that there are small but significant differences in OMFD kinetics in different parts of the brain that may prevent inferences about the handling of OMFD in one part of the brain from being extended to other parts of the brain. Key Words: Compartmental analysis-Dopamine metabo lism-6-Fluoro-3-0-methyl-L-dopa-6-Fluoro-L-dopa Graphical analysis-Positron tomography-Striatum. methyltransferase (COMT), forming eSF16-fluoro-3-0-methyl-L-dopa (OMFD). OMFD, formed in the peripheral organs and the red blood cells, is able to cross the blood-brain barrier and contributes to the radioactivity measured by the tomograph. Correc tions for this radioactivity in dopaminergic regions of the brain have been proposed (Martin et aI. , 1989; Huang et aI. , 1991; Gjedde et aI. , 1991; Chan et aI., 1992). These corrections usually rely upon one or more of the following assumptions: t...

Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine

“…In the calculation of ordinate values, the radioactivity concentrations in CB were subtracted from those in each ROI to correct for the presence of non-specific background tissue radioactivity -i.e. that due primarily to O-methyl-FDOPA, the major peripheral metabolite of FDOPA which, unlike FDOPA, displays nearly uniform uptake and distribution throughout living human brain (Wahl et al, 1994). A coefficient of in situ FDOPA decarboxylation (k 3 r , min Ϫ1 ) was estimated from the linear regression slope of this plot.…”

Mapping of central dopamine synthesis in man, using positron emission tomography with l-[β-11C]DOPA

“…To assess the endogenous dopamine synthesis rate, one of the presynaptic functions, carbon-11 labeled L-DOPA (L-[β-11 C]DOPA) and fl uorine-18 labeled L-DOPA (6-[ 18 F]fl uoro-L-DOPA) are used as positron emission tomography (PET) tracers [1][2][3][4][5][6]. The 3-O-methyl metabolite of L-DOPA crossing the blood-brain barrier causes error in the estimation of dopamine synthesis rate [7][8][9], and 3-O-methylation of L-[β-11 C]DOPA does not take place readily and rapidly when compared with 6-[ 18 F]fl uoro-L-DOPA [7,10,11]. For quantitative analysis of L-[β- 11 C]DOPA kinetics in the brain, a graphical analysis method developed by Gjedde and Patlak et al [1,12], in which a reference brain region with no irreversible binding is employed to preclude the need for an arterial input function, has been widely used.…”

PET 6-[18F]fluoro-L-m-tyrosine studies of dopaminergic function in human and nonhuman primates

“…While FDOPA is well validated as a dopaminergic tracer (Eidelberg et al, 1994; Pate et al, 1993; Vingerhoets et al, 1994), it has the disadvantage of being subject to peripheral metabolism by catechol-O-methyltransferase (COMT). The resulting methylated metabolites are transported across the blood-brain barrier by the large neutral amino acid transporter and contribute to the PET signal in the brain thereby degrading the signal to noise ratio and complicating kinetic modeling (Doudet et al, 1991; Wahl et al, 1994). An alternative AADC tracer, 6-[ 18 F]fluoro-L-m-tyrosine (FMT), is not subject to O-methylation resulting in better quality images with higher signal to noise and more straightforward kinetics (DeJesus et al, 1997; Jordan et al, 1997; Nahmias et al, 1995).…”