Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: Implications for compartmental modelling and clinical usefulness

Abstract

The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[18F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [18F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K1D) and net (Ki) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k3D) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k3D were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k3D increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates.

Microdialysis with Radiometric Monitoring of L-[β-11C]DOPA to Assess Dopaminergic Metabolism: Effect of Inhibitors of L-Amino Acid Decarboxylase, Monoamine Oxidase, and Catechol-O-Methyltransferase on Rat Striatal Dialysate

“…Plasma [ 11 C]3-OMD gradually increased up to 20 minutes after intravenous L-[b-11 C]DOPA until total 11 C-radioactivity was derived from [ 11 C]3-OMD and L-[b-11 C]DOPA in a 1:1 ratio ( Figure 5). Radioactive 3-OMD can be detected in plasma (Leger et al, 1998;Tsukada et al, 1994) and increases gradually (as observed here). The [ 11 C]3-OMD levels in striatal ECF are low after intrastriatal administration of L-[b-11 C]DOPA (data not shown), suggesting that Ishikawa et al, 1996;Leger et al, 1998).…”

“…Radioactive 3-OMD can be detected in plasma (Leger et al, 1998;Tsukada et al, 1994) and increases gradually (as observed here). The [ 11 C]3-OMD levels in striatal ECF are low after intrastriatal administration of L-[b-11 C]DOPA (data not shown), suggesting that Ishikawa et al, 1996;Leger et al, 1998). In addition, a high concentration of 3-OMD in plasma and cerebrospinal fluid is detected in Parkinson's disease with chronic levodopa therapy, which causes dyskinesia (Benetello et al, 1997;Hardie et al, 1986;Tohgi et al, 1991) and oxidative stress (Lee et al, 2008).…”

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

“…Second, graphical analysis of unidirectional FDOPA clearance has been applied previously to brain TACs that are incompletely corrected for OMFD, which ultimately constitutes the majority of radioactivity in most brain regions Leger et al, 1998). These approximations in pharmacokinetic analysis result in biased estimates of the rate of substrate utilization , whereas failing to correct for the turnover of […”

“…should be in a constant ratio (q) (Gjedde et al, 1991) of magnitude fixed at 1.5 based on the mean of all published estimates and based on a systematic study of the effect of q on the calculation of FDOPA kinetics (Leger et al, 1998). The global brain TAC of OMFD for each experimental subject was then recovered from the following calculation:…”

Subchronic Haloperidol Downregulates Dopamine Synthesis Capacity in the Brain of Schizophrenic Patients In Vivo

“…In the present model, the two amino acids O-methyl-FDOPA and FDOPA are assumed to have a single common distribution volume, and are assumed to have a fixed permeability ratio, q, of 1.5, based upon the mean of several estimates . The sensitivity of the estimation of k D 3 to the constrained values of q and V e D was investigated in the monkey brain (Léger et al, 1998).…”