18F-labeled FECNT: a selective radioligand for PET imaging of brain dopamine transporters.

Fluorine-18 labeled 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (FECNT) was synthesized in the development of a dopamine transporter (DAT) imaging ligand for positron emission tomography (PET). The methods of radiolabeling and ligand synthesis of FECNT, and the results of the in vitro characterization and in vivo tissue distribution in rats and in vivo PET imaging in rhesus monkeys of [18F]FECNT are described. Fluorine-18 was introduced into 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (4) by preparation of 1-[18F]fluoro-2-tosyloxyethane (2) followed by alkylation of 2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (3) in 21% radiochemical yield (decay corrected to end of bombardment [EOB]). Competition binding in cells stably expressing the transfected human DAT serotonin transporter (SERT) and norepinephrine transporter (NET) labeled by [3H]WIN 35428, [3H]citalopram, and [3H]nisoxetine, respectively, indicated the following order of DAT affinity: GBR 12909 > CIT >> 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(3-fluoropropyl) nortropane (FPCT) > FECNT. The affinity of FECNT for SERT and NET was 25- and 156-fold lower, respectively, than for DAT. Blocking studies were performed in rats with a series of transporter-specific agents and demonstrated that the brain uptake of [18F]FECNT was selective and specific for DAT-rich regions. PET brain imaging studies in monkeys demonstrated high [18F]FECNT uptake in the caudate and putamen that resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 10.5 at 60 min. [18F]FECNT uptake in the caudate/putamen peaked in less than 75 min and exhibited higher caudate- and putamen-to-cerebellum ratios at transient equilibrium than reported for 11C-WIN 35,428, [11C]CIT/RTI-55, or [18F]beta-CIT-FP. Analysis of monkey arterial plasma samples using high performance liquid chromatography determined that there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In equilibrium displacement experiments with CIT in rhesus monkeys, radioactivity in the putamen was displaced with an average half-time of 10.2 min. These results indicate that [18F]FECNT is a radioligand that is superior to 11C-WIN 35,428, [11C]CIT/RTI-55, [18F]beta-CIT-FP, and [18F]FPCT for mapping brain DAT in humans using PET.

Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors.

UNLABELLED: We have developed a new tumor-avid amino acid, 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC), labeled with 18F for nuclear medicine imaging. METHODS: [18F]FACBC was prepared with high specific activity (no carrier added [NCA]) and was evaluated for its potential in tumor localization. A comparative study was performed for [18F]FACBC and [18F]2-fluorodeoxyglucose (FDG) in which the uptake of each agent in 9L gliosarcoma (implanted intracerebrally in Fisher 344 rats) was measured. In addition, the first human PET study of [18F]FACBC was performed on a patient with residual glioblastoma multiforme. Quantitative brain images of the patient were obtained by using a Siemens 921 47-slice PET imaging system. RESULTS: In the rat brain, the initial level of radioactivity accumulation after injection of [18F]FACBC was low (0.11 percentage injected dose per gram [%ID/g]) at 5 min and increased slightly to 0.26 %ID/g at 60 min. The tumor uptake exhibited a maximum at 60 min (1.72 %ID/g), resulting in a tumor-to-brain ratio increase of 5.58 at 5 min to 6.61 at 60 min. In the patient, the uptake of [18F]FACBC in the tumor exhibited a maximum concentration of 146 nCi/mL at 35 min after injection. The uptake of radioactivity in the normal brain tissue was low, 21 nCi/mL at 15 min after injection, and gradually increased to 29 nCi/mL at 60 min after injection. The ratio of tumor to normal tissue was 6 at 20 min after injection. The [18F]FACBC PET scan showed intense uptake in the left frontal region of the brain. CONCLUSION: The amino acid FACBC can be radiofluorinated for clinical use. [18F]FACBC is a potential PET tracer for tumor imaging.

Fluorine-18-FPCT: a PET radiotracer for imaging dopamine transporters.

UNLABELLED: Fluorine-18-labeled 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-[-3-fluoropropyl) nortropane (FPCT) has been synthesized as a new dopamine transporter imaging agent. METHODS: Fluorine-18 was introduced into 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-[-3-fluoropropyl) nortropane by preparation of 1-[18F]fluoro-3-iodopropane followed by alkylation of 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)nortropane. RESULTS: Tissue distribution studies in rats with [18F]FPCT showed high striatal uptake (0.70% dose/g at 60 min; 0.38% dose/g at 120 min) and good striatal-to-cerebellum ratios (5.5 at 60 min; 6.2 at 120 min). Imaging studies in rhesus monkeys (n = 2) with [18F]FPCT showed high uptake and retention in the putamen (P) (P = 0.03%-0.12% dose/g; at 115 min) and good putamen-to-cerebellum ratios of 3.40-3.43 at 115 min. Plasma metabolites were analyzed in rhesus monkeys (n = 2) by ether extraction and HPLC. The radioactivity in the ether-extractable fraction displayed a single peak that corresponded on HPLC to unmetabolized authentic FPCT. CONCLUSION: These results suggest that [18F]FPCT is an excellent candidate for PET imaging of dopamine transporters.

Platelet monoamine oxidase activity in alcoholics, alcoholics with drug dependence, and cocaine addicts.

The main objective of this investigation was to study the influence of drug dependence on platelet monoamine oxidase (MAO) activity in the presence and absence of alcoholism. One hundred and thirteen admissions to alcohol and drug treatment facilities participated in the study. Twenty-six met the criteria for alcoholism (group I), seventy-eight subjects were alcohol-/cocaine- and cannabis-dependent (group II), and the remaining nine were patients with DSM-III-R diagnosis of cocaine addiction (group III). MAO activity was assayed radiochemically with [14C]tyramine as a substrate (221 microM). The results of this study showed that platelet MAO activity [nmol of product formed x (mg protein)-1 x hr-1] (mean +/- SE) was significantly (p < 0.01) lower in all of these subjects (group I, 5.50 +/- 0.80; group II, 3.90 +/- 0.50; group III, 4.3 +/- 1.60) as compared with controls (14.85 +/- 1.13). Measurements of platelet MAO activity may provide us with a reliable biochemical marker for alcoholism and perhaps addiction to other substances of abuse (i.e., cocaine).

The effect of cocaine abuse on plasma levels of sulfated dopamine and salsolinol in alcoholics.

This study investigated the effect of cocaine abuse on peripheral dopamine and its tetrahydroisoquinoline metabolite salsolinol in chronic alcoholics. Specifically, the concentration of dopamine sulfate and salsolinol sulfate was measured in plasma samples obtained from the blood of a group of alcoholics (n = 40) and alcoholics with cocaine dependence (n = 55). The concentrations of sulfoconjugated dopamine and salsolinol were measured by a radioenzymatic technique. The results of this study showed that chronic alcoholics (627 +/- 195 pg/ml) and alcoholics with cocaine addiction (409 +/- 76 pg/ml) had significantly (p < 0.05) elevated levels of salsolinol sulfate (mean +/- SEM) in their plasma as compared to controls (99.5 +/- 7.5 pg/ml). However, alcoholics with cocaine dependence produced significantly (p < 0.01) higher concentration of dopamine sulfate in their plasma (7520 +/- 1299 pg/ml) as compared to chronic alcoholics (3896 +/- 438 pg/ml) and controls (2124 +/- 104 pg/ml). Differences in plasma dopamine sulfate among alcoholics with cocaine dependence vs. alcoholics without cocaine dependence may be interpreted as a reflection of increased extracellular dopamine metabolism associated with chronic cocaine exposure.

Elevated concentrations of dopamine sulfate in plasma of cocaine abusers.

This study investigated the effect of cocaine abuse on peripheral catecholamines. Specifically, we measured the concentration of free dopamine, dopamine sulfate, free norepinephrine, norepinephrine sulfate, free epinephrine and epinephrine sulfate in plasma samples obtained from the blood of a group of patients with cocaine addiction (N = 15). The concentrations of free and sulfoconjugated catecholamines in plasma were measured by a radioenzymatic technique. The results of this study revealed significant (P < 0.0001) elevation in plasma dopamine sulfate (8926 +/- 1204 pg/mL) of cocaine addicts upon admission to an in-patient treatment facility when compared with the level of this dopamine metabolite in plasma of control subjects (2356 +/- 121 pg/mL). Furthermore, there was a significant (P < 0.0001) relationship between elevation in plasma dopamine sulfate levels and severity of cocaine use among these patients, and in the majority of cases the plasma levels of dopamine sulfate declined appreciably in time with abstinence from cocaine. In contrast, no appreciable difference was observed in the concentrations of either free or sulfate-conjugated norepinephrine and epinephrine in plasma of cocaine addicts as compared with controls. Differences in plasma dopamine sulfate among these patients versus controls may be interpreted as a reflection of activation of extracellular dopamine metabolism associated with chronic cocaine exposure in humans.

Interrelationship between activation of dopaminergic pathways and cerebrospinal fluid concentration of dopamine tetrahydroisoquinoline metabolite salsolinol in humans: preliminary findings.

The main objective of this study was to determine whether the activation of dopaminergic pathways, through adrenal-caudate transplantation, stimulated the production of dopamine and salsolinol in cerebrospinal fluid (CSF) of patients with Parkinson's disease. Dopamine sulfate and salsolinol sulfate in CSF specimens were measured by radioenzymatic technique. The results of this study demonstrated that the replacement of degenerative nigrostriatal neurons with new dopamine-producing cells by adrenal brain transplants in patients with Parkinson's disease resulted in significant increase (p less than 0.05) in CSF levels of free dopamine, dopamine sulfate, free salsolinol, and salsolinol sulfate as compared with preoperative levels. Moreover, the oral administration of L-dopa to these transplanted patients caused substantial (p less than 0.001) elevation in CSF levels of free dopamine (before L-dopa, 146 +/- 57 pg/ml; after L-dopa, 575 +/- 207 pg/ml), dopamine sulfate (before L-dopa, 1966 +/- 945 pg/ml; after L-dopa, 41679 +/- 29326 pg/ml), free salsolinol (before L-dopa, 43 +/- 29 pg/ml; after L-dopa, 186 +/- 90 pg/ml), and salsolinol sulfate (before L-dopa, 405 +/- 477 pg/ml; after L-dopa, 2908 +/- 2572 pg/ml), respectively.

Abnormal vitamin B6 status in childhood leukemia.

Vitamin B6 is involved in many biological processes of potential relevance to carcinogenesis and tumor growth, including DNA synthesis and maintenance of immunocompetence, yet very little information exists on B6 nutritional status in childhood leukemia. Using a radioenzymatic assay, the authors measured plasma pyridoxal 5'-phosphate (PLP), the biologically active form of B6, in 11 newly diagnosed untreated children with leukemia and 11 age-matched controls. The children with leukemia had significantly lower PLP levels than the controls. In 26 additional leukemia patients and 26 additional controls, a high-performance liquid chromatography assay also demonstrated lower plasma PLP levels in childhood leukemia compared with controls. These differences were significant for both acute lymphoblastic leukemia (ALL) and for acute nonlymphoblastic leukemia (ANLL). The PLP values did not correlate with indices of leukemia cell burden, but did correlate with reported B6 intake, suggesting that illness-related diet changes are at least partially responsible for the low PLP levels. Before any chemotherapy, overall nutritional status was suboptimal in 53% of ALL cases and 57% of ANLL cases. Newly diagnosed children with leukemia have suboptimal overall nutrition as well as suboptimal vitamin B6 status.

Effect of adrenal-caudate transplantation on CSF levels of salsolinol sulfate in patients with Parkinson's disease.

The main objective of this study was to determine whether the activation of dopaminergic pathways through adrenal-caudate transplantation stimulates the production of the dopamine cyclic metabolite salsolinol in CSF of patients with Parkinson's disease. Salsolinol sulfate in CSF samples was assayed by radioenzymatic technique. The outcome of this study revealed that the replacement of degenerative nigrostriatal neurons with new dopamine-producing cells by adrenal brain transplants resulted in significant increase in CSF concentration of salsolinol sulfate as compared to preoperative levels.

Effects of protamine on histamine release from human lung.

Animal mast cell models demonstrate direct histamine release by protamine. Investigators have proposed that protamine also releases histamine in man. We studied the effects of protamine alone and heparin-protamine mixtures on minced lung tissue for evidence of histamine release. We were unable to demonstrate the release of histamine despite positive anti-IgE controls. Nonimmunologic histamine release from human lung appears unlikely as a mechanism for protamine reactions in man.

Elevation of plasma salsolinol sulfate in chronic alcoholics as compared to nonalcoholics.

This report describes a radioenzymatic assay for the measurement of salsolinol and dopamine sulfate levels in plasma. It is based on a sulfatase-catalyzed hydrolysis of the sulfoconjugates followed by catechol-O-methyltransferase and [methyl-3H]-S-adenosylmethionine-catalyzed O-methylation of the resulting free salsolinol and dopamine. Rapid thin-layer chromatographic separation of the formed labeled metabolites attributed to the specificity of the differential enzymatic assay of salsolinol and dopamine. This assay was used to study plasma salsolinol and dopamine levels in a group of adult males (n = 36) serving as controls and a group of hospitalized chronic alcoholics (n = 18). The results (mean and range) of this preliminary study show that alcoholics had significantly (p less than 0.0001) elevated plasma concentration of salsolinol sulfate (497; 50-1331 pg/ml) as compared to controls (93; 0-232 pg/ml). This was accompanied by significant (p less than 0.0003) elevation in plasma levels of dopamine sulfate. Elevation of plasma salsolinol sulfate reported here may be interpreted as a reflection of abnormalities in oxidative metabolism of dopamine, metabolically derived acetaldehyde, and/or biological carbonyls in chronic alcoholics.

Pyridoxal 5'-phosphate levels in children with sickle cell disease.

Pyridoxal 5'-phosphate (PLP), the major coenzyme form of vitamin B6, is known to have antisickling properties in vitro. Recently, low plasma PLP levels were reported in a group of adults with sickle cell anemia. We measured the plasma PLP levels in a group of 55 asymptomatic nontransfused children with sickle cell diseases (SCD) to determine the prevalence of low plasma PLP levels in this population. Comparative studies were made with the measurement of PLP in three other groups serving as controls: Group A (black children, n = 36); Group B (white children, n = 37); and Group C (black adults, n = 13). PLP was measured directly in plasma by a radioenzymatic technique. The results of these comparisons showed that there was no statistically significant difference in plasma PLP of black children with SCD (10.7 +/- 10.0 ng/ml) as compared with black control children (group A, 9.0 +/- 12.3 ng/ml). The low plasma levels PLP in these two groups were significantly lower than that of the plasma PLP of white control children (group B, 15.85 +/- 15.92 ng/ml). This data suggest that a high prevalence of low PLP levels exists in black children seen at Grady Memorial Hospital, both with and without SCD.

Prevalence of low monoamine oxidase function in alcoholism.

Several studies have found a trend for low platelet monoamine oxidase activity (MAO) in alcoholism but with a great deal of overlap in MAO activity of alcoholics versus controls. The main objective of this study was to carry out a detailed assessment of MAO function that included the measurement of key kinetic parameters (i.e., Km, Vmax) in three groups of male subjects: (a) 51 hospitalized chronic alcoholics, (b) 16 recovering alcoholics with 2-10 years of abstinence, and (c) 21 controls. MAO activity was assayed radiochemically with [14C]tyramine as substrate (43-729 microM). The present study demonstrated that alcoholics had low platelet MAO activity (p less than 0.05). Kinetic analysis revealed a substantial reduction (p less than 0.01) in enzyme Vmax values of chronic and recovering alcoholics. Greater than 95% of the alcoholics had Vmax values lower than the smallest value of control subjects. Moreover, 100% of the alcoholics in both groups exhibited exceedingly low Vmax values that were below the 25th percentile of controls. In summary, results of MAO Vmax determinations provided us with a better separation of the alcoholics from controls. Measurements of platelet MAO function that include enzyme Vmax may provide us a reliable biochemical marker for alcoholism.

Tyramine neurotoxicity and first-pass brain technetium-99m-diethylenetriamine penta-acetic acid.

Tyramine induces coma in phenelzine-treated dogs with liver disease. The objective of the present investigation was to examine the influence of tyramine in these monoamine oxidase-inhibited dogs on the kinetics of Tc-99m-diethylenetriamine penta-acetic acid (Tc-99m-DTPA) during its first passage through the brain by nuclear imaging techniques. The study began with anesthetized mongrel dogs (n = 10) in a supine position over the camera detector. Data acquisition was started simultaneously after the rapid intracarotid injection of Tc-99m-DTPA (5 mCi) and 60 0.5-sec images of the brain were taken. Tyramine induced increased uptake with a concomitant impairment in the elimination of Tc-99m-DTPA from the brain of these phenelzine-treated animals with hepatic injury (n = 5) as compared to pretreated animals serving as a control group or phenelzine-treated animals without liver disease. This was accompanied by an appreciable reduction in hemispheric cerebral blood flow (50.5 +/- 19.3 vs. 110 +/- 16 ml/100 g/min), respectively. Increased cerebrovascular permeability of Tc-99m-DTPA and decreased cerebral blood flow occurred concomitantly with increased cerebrospinal fluid pressure and elevation in cerebrospinal fluid catecholamines of monoamine oxidase-inhibited animals with hepatic injury.

Histamine-dependent allergy blood test. Clinical evaluation.

Allergen-mediated histamine release from human leukocytes represents an important model for in vitro studies of allergic reactions. The purpose of this study was to determine whether the measurement of histamine released in allergic patients by radioenzymatic assay following mixing of their blood with common allergens represents a reliable index for diagnosis of atopic allergy. Three categories of allergens were used: 1) house dust and mite; 2) cat and dog dander; 3) trees, grasses and ragweed mixture. The presence of allergy was established by clinical history and intradermal skin testing in the study group of 150 patients. A significant allergen-mediated histamine release ranging from 4 to 65% of the total blood histamine content was observed in 96% of the patients with skin test sensitivity of greater than or equal to 3+. There was a significant correlation between skin testing and histamine release in terms of the allergens causing the response. Thus, the measurement of histamine by radioenzymatic technique following its release in blood in response to allergen challenge represents a clinically useful in vitro test for the diagnosis of atopic disease.

Low levels of pyridoxal 5'-phosphate in patients with cystic fibrosis.

To determine the effect of cystic fibrosis on the regulation of plasma pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6, we measured this compound in plasma from 56 patients with cystic fibrosis. The concentration of PLP in plasma was assayed by a radioenzymatic technique. The results of this study showed that PLP concentration was decreased significantly (6.44 +/- 5.20 ng/mL, mean +/- SD; median 4.45 ng/mL) in patients with cystic fibrosis as compared with a group of hospitalized children with neither cystic fibrosis nor hepatic disease serving as a control group (13.2 +/- 5.04 ng/mL, mean +/- SD; median 12.5 ng/mL). Additionally, 25% of the population with cystic fibrosis exhibited exceedingly low plasma PLP level (less than 2.75 ng/mL). In patients with cystic fibrosis, significant inverse linear associations were found between plasma PLP and serum levels of SGOT and SGPT (PLP v SGOT: r = -.60, P less than .03; PLP v SGPT: r = -.50, P less than .03). This study demonstrated that a deficiency of plasma PLP is a common abnormality in cystic fibrosis and that the low PLP level may be a reflection of impaired vitamin B6 metabolism associated with this disorder.

Plasma L-dopa in the diagnosis of malignant melanoma.

We determined the concentration of L-dopa in the plasma of 98 patients with biopsy-proven melanoma, a dermatological neoplasm that is characterized biochemically by abnormal tyrosine metabolism. For 21 patients previously diagnosed as having melanoma but who were clinically free of disease (stage I), the mean concentration of L-dopa in plasma, 1.01 (SD 0.12) micrograms/L, was not significantly different from that of 32 normal controls, 1.23 (SD 0.16) micrograms/L. However, L-dopa was increased significantly (p less than 0.001) in the plasma of all of 65 patients with active disease (stage II), 2.08 (SD 0.46) micrograms/L, and was highest in 12 patients with stage III malignant melanoma, 8.40 (SD 3.50) micrograms/L. The development of metastases in four patients with stage II melanoma was accompanied by an increase in the concentration of plasma L-dopa. These studies suggest that measurement of plasma L-dopa may be useful in the diagnosis of melanoma.

Plasma dopa and catecholamines in the diagnosis and follow-up of children with neuroblastoma.

Plasma dopa and the catecholamines--dopamine, norepinephrine, and epinephrine--were assayed by a radioenzymatic method in 15 children with active neuroblastoma and in eight others without evidence of disease to assess the value of these determinations in the diagnosis and management of the tumor. Thirty-four children with solid tumors and hemopoietic malignancies served as our controls. Elevated plasma dopa levels were observed in 13 children with active neuroblastoma (87%); dopamine and norepinephrine were elevated in 1/4 of these patients. In the group of children with neuroblastoma without evidence of disease, dopa and catecholamine levels were within the range observed in the controls. Total urinary catecholamines, homovanillic acid (HVA) and/or vanilmandelic acid (MVA) were elevated in 11 of the 15 (73%) neuroblastoma patients with active disease. While serial plasma dopa determinations correlated with the course of the disease in practically all patients and thus were useful in their follow-up, the catecholamines were of limited value in assessing tumor status. Our results suggest that plasma dopa, assayed by a radioenzymatic method, may be more reliable than the traditional urinary catecholamine determinations in the diagnosis of neuroblastoma, and it appears useful in the management of this disease.

Hypercatecholaminemia in Reye's syndrome.

To evaluate the role of catecholamines in Reye's syndrome, a specific and sensitive radioenzymatic assay was used to study plasma and CSF concentration of dopamine, norepinephrine, and epinephrine in 14 patients with liver-biopsy-proven Reye's syndrome. The results (median and range) revealed significant (P less than .04, P less than .0024, and P less than .030, respectively) elevation in plasma dopamine (131, 0 to 1,193 pg/mL), norepinephrine (1,455, 20 to 5,271 pg/mL), and epinephrine (345, 7.6 to 2,504 pg/mL) at the onset of the disease when compared with the level of these neurotransmitters in a group of hospitalized patients without hepatic disorders. There was a positive correlation between plasma catecholamines and stage of coma on admission (r = .54 to .86; P less than .001 to .024). Furthermore, the concentration of dopamine, norepinephrine, and epinephrine in the CSF increased significantly during the development of cerebral edema in all patients with Reye's syndrome as compared with concentrations in a control population. Hypercatecholaminemia may contribute to the encephalopathy of Reye's syndrome.