[Axelrod et al. (1958)][1] first described the enzyme-catalyzed O- methylation of catecholamines and other catechols in the late 1950s. The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT; EC[2.1.1.6][2]),2 was partly purified and characterized by the same group ([

Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Both environmental and genetic factors contribute to the etiology of this complex disease. In the current investigation, a catechol-O-methyltransferase (COMT) polymorphism that codes for a high versus low enzyme COMT activity was examined using family-based methods for a role in ADHD. Using a haplotype relative risk design and a parent-to-proband allele transmission test with 48 ADHD triads, we found an association between COMT and illness (χ2 = 4.72, p = 0.03, df = 1). In particular, the impulsive-hyperactive type of ADHD (excluding inattention) ascertained by Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria (χ2 = 8.34, p = 0.004, df = 1), by the Conners Teaching Rating Hyperactivity scale (Pearson χ2 = 5.32, p = 0.02, df = 1) as well as by the Continuous Performance Test False Alarm scale (χ2 = 2.78, p = 0.096, df = 1) were associated with the high enzyme activity COMT val allele. Similar results were obtained if genotype frequencies were compared. It should be noted that the association between the high-enzyme activity COMT val allele that increases CNS dopamine (and norepinephrine) clearance is consistent with the use of methylphenidate, an agent that increases dopamine (and norepinephrine) turnover, in the treatment of this disorder. These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinson's disease, might in due time be considered in the treatment of ADHD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:497–502, 1999. © 1999 Wiley-Liss, Inc.

Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype.

The trapping of decarboxylation products of radiolabelled dopa analogs in living human brain occurs as a function of the activity of dopa decarboxylase. This enzyme is now understood to regulate, with tyrosine hydroxylase, cerebral dopamine synthesis. Influx into brain of dopa decarboxylase substrates such as 6-[18F]fluorodopa and beta-[11C]dopa measured by positron emission tomography can be analyzed by solution of linear differential equations, assuming irreversible trapping of the decarboxylated products in brain. The isolation of specific physiological steps in the pathway for catecholamine synthesis requires compartmental modelling of the observed dynamic time-activity curves in plasma and in brain. The several approaches to the compartmental modelling of the kinetics of labelled substrates of dopa decarboxylase are now systematically and critically reviewed. Labelled catechols are extensively metabolized by hepatic catechol-O-methyltransferase yielding brain-penetrating metabolites. The assumption of a fixed blood-brain permeability ratio for O-methyl-6-[18F]fluorodopa or O-methyl-beta-[11C]dopa to the parent compounds eliminates several parameters from compartmental models. However, catechol-O-methyltransferase activity within brain remains a possible factor in underestimation of cerebral dopa decarboxylase activity. The O-methylation of labelled catechols is blocked with specific enzyme inhibitors, but dopa decarboxylase substrates derived from m-tyrosine may supplant the catechol tracers. The elimination from brain of decarboxylated tracer metabolites can be neglected without great prejudice to the estimation of dopa decarboxylase activity when tracer circulation is less than 60 minutes. However, elimination of dopamine metabolites from brain occurs at a rate close to that observed previously for metabolites of glucose labelled in the 6-position. This phenomenon can cause systematic underestimation of the rate of dopa decarboxylation in brain. The spillover of radioactivity due to the limited spatial resolution of tomographs also results in underestimation of dopa decarboxylase activity, but correction for partial volume effects is now possible. Estimates of dopa decarboxylase activity in human brain are increased several-fold by this correction. Abnormally low influx of dopa decarboxylase tracers in the basal ganglia is characteristic of Parkinson's disease and other movement disorders. Consistent with postmortem results, the impaired retention of labelled dopa is more pronounced in the putamen than in the caudate nucleus of patients with Parkinson's disease; this heterogeneity persists after correction for spillover. Current in vivo assays of dopa decarboxylase activity fail to discriminate clinically distinct stages in the progression of Parkinson's disease and are, by themselves, insufficient for differential diagnosis of Parkinson's disease and other subcortical movement disorders. However, potential new avenues for therapeutics can be tested by quantifying the rate of metabolism of exogenous dopa in living human brain.

Compartmental analysis of dopa decarboxylation in living brain from dynamic positron emission tomograms

Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease.

New, Selective Catechol-O-Methyltransferase Inhibitors as Therapeutic Agents in Parkinson’s Disease

Effects of monoamine oxidase and catechol-O-methyltransferase inhibition on dopamine turnover : A pet study with 6-[18F]L-DOPA

Summary: This article describes a simplified method for the determination of the L-[18F]6-fluorodopa (FDOPA) fraction time course that takes advantage of the strong correlation between the radioactivity ratio (metabolites/ FDOPA) and time. Serial arterial blood samples are collected for assay of plasma total radioactivities following an intravenous injection of FDOPA into carbidopa-pretreated subjects. In addition, a single plasma sample, collected late in the study and analyzed for FDOPA fraction, is sufficient to determine accurately the time course of the FDOPA concentration in plasma. The validated straight-line method greatly simplifies blood analysis for routine positron emission tomography FDOPA studies.

Plasma L-[18F]6-fluorodopa input function: a simplified method.

The Reproducibilityof Stnatal Uptake Data Obtained with Positron Emission Tomography

The reproducibilityof (Â±)-a-(11C) dihydrotetrabenazine (DTBZ) measuresin PET was studied in 10 healthyhumansubjects, aged22â€"76 y. Methods: The scan-to-scanvariationof several measuresusedin PETdataanalysiswasdetermined,including the radioactivityratio (target-to-reference), plasma-inputLogan total distributionvolume(DV),plasma-inputLogan @ and tissue-inputLogan B@JKIJ values. Results: The radioactivity ratios, plasma-inputB@,JK,J and tissue-inputBr,@R,JKJ all have higherreliabilitythan plasma-inputtotal DV values.In addition, measuresusingtheoccipitalcortexasthe referenceregionhave higherreliabilitythan the samemeasuresusingthe cerebellum as the referenceregion. Conclusion: Our results show that DTBZis a reliablePETtracerthat providesreproduciblein vivo measurementof striatalvesicularmonoaminetransporterden sity. In the selectionof referenceregionsfor DTBZ PET data analysis, caution must be exercisedin circumstanceswhen DTBZbindingin the occipital cortexor thecerebellum maybe altered.

K. Scott Morrison

Papers

Effects of monoamine oxidase and catechol-O-methyltransferase inhibition on dopamine turnover : A pet study with 6-[18F]L-DOPA

Plasma L-[18F]6-fluorodopa input function: a simplified method.

The Reproducibilityof Stnatal Uptake Data Obtained with Positron Emission Tomography

Reproducibility Studies with â€˜1C-DTBZ, a Monoamine Vesicular TransporterInhibitorin Healthy Human Subjects