Karl-Johan Lindner

Central nervous system effects of subdissociative doses of (S)‐ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)‐ketamine were measured in a randomized, double‐blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)‐[N‐methyl‐11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N‐methyl‐D‐aspartate receptor complexes. A significant and dose‐dependent reduction of binding was measured as a result of displacement of (S)‐[N‐methyl‐11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)‐ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)‐ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)‐ketamine, measured with positron emission tomography, can be related directly to drug effects.

Demonstration of [11C] 5-hydroxy-L-tryptophan uptake and decarboxylation in carcinoid tumors by specific positioning labeling in positron emission tomography

In three patients with carcinoid liver and/or lymph node metastases, we studied the process of tumor tracer uptake and decarboxylation by means of positron emission tomography (PET) using 5-hydroxy-L-tryptophan (5-HTP) 11C-labeled in the beta-position (HTP) and later the same day with 5-HTP 11C-labeled in the carboxyl group (HTC). With HTP, in which the 11C-label follows the molecule through decarboxylation to form 11C-serotonin, a high tumor accumulation of the tracer was found. With HTC, in which the label is rapidly eliminated from the tissues as 11CO2 if decarboxylation takes place, there was virtually no uptake by the tumors. By utilizing data from PET scanning with both tracers, we could quantify the decarboxylation rate and tissue accumulation of [11C]-serotonin and hence the enzymatic action of aromatic amino acid decarboxylase.

Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography

The influence of the co-factor pyridoxine, vitamin B6, on the activity of aromatic amino acid decarboxylase enzyme was studied by positron emission tomography, PET in the brain of the Rhesus monkey using the precursor for serotonin synthesis 5-hydroxy-L-tryptophan (5-HTP) radiola-belled with11C in the β-position. The rate constant for the formation of serotonin in the corpus striatum was calculated using a two tissue compartment model with reference area in the brain. In baseline investigations, the mean rate constants (±S.D:) for selective utilization of [11C]5-HTP to form [11C]serotonin in the corpus striatum was 0.0080 ± 0.0011 min−1. Pretreatment with intravenous pyridoxine hydrochloride 10 mg/kg bodyweight before doing a second PET study resulted in an enhanced rate constant by a mean of 20%. The rate increase was statistically significant. The increase varied considerably in different monkeys from no effect to more than 60%. The effect of pyridoxine on aromatic amino acid decarboxylase activity supported a regulatory role of pyridoxine on the synthesis of neurotransmitter in vivo, and may be of importance in diseases with deficiencies in neurotransmitter function.

Regional brain kinetics of 6-fluoro-(β-11C)-L-dopa and (β-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography

The regional brain kinetics of (β-11C)-L-dopa and 6-fluoro-(β-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 ± 0.0007 (S.D) and 0.0057 ± 0.0006 min1 for (β-11C)-L-dopa and 6-fluoro-(β-11C)-L-dopa, respectively. After pre-treatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 ± 0.0015 min-1) for (β11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(β-11C)L-dopa (0.0092 ± 0.0015 min−1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(β-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(β-11C)-L-dopa significantly contributes to background radioactivity.

Brain kinetics of 11 C-labelled L-tryptophan and 5-hydroxy-L-tryptophan in the rhesus monkey. A study using positron emission tomography.

5-Hydroxy-L-tryptophan labelled with 11 C is introduced as a tracer for the in vivo assessment of brain serotonin synthesis in the Rhesus monkey using positron emission tomography, PET. Increasing radioactivities were seen in the striatal area in contrast to that seen in other brain regions. Following 11 C-labelled L-tryptophan an even spread of brain radioactivity was seen. This selective increase most probably results from the decarboxylation of tracer and retention of formed products since no striatal increase of radioactivity was seen when 5-hydroxy-L-tryptophan labelled with 11 C in the carboxy-position was administered. Furthermore, pretreatment of the monkey with a centrally active decarboxylase inhibitor (NSD 1015,10 mg/kg) did not lead to increased striatal radioactivities after the administration of 5-hydroxy-(β-11C)-L-tryptophan. The selective utilization of the radiotracer in the striatal area increased with a rate constant calculated to be 0.0055 ± 0.0015 min−1 (n = 5) using the surrounding brain as reference area. A non-significant influence of radiolabelled metabolites to the rate constants measured was shown after pretreatment of the monkeys with selective and non-selective monoamine oxidase inhibitors, respectively. These results may give a basis for the use of the new tracer 5-hydroxy-(β-11 C)-L-tryptophan in PET-studies of brain serotonin metabolism in health and disease.

Positron emission tomographic studies on aromatic L-amino acid decarboxylase activity in vivo for L-dopa and 5-hydroxy-L-tryptophan in the monkey brain

The regional brain kinetics following 5-hydroxy-L-(β-11 C)tryptophan and L-(β-11 C)DOPA intravenous injection was measured in twelve Rhesus monkeys using positron emission tomography (PET). The radiolabelled compounds were also injected together with various doses of unlabelled 5-hydroxy-L-tryptophan or L-DOPA. The radioactivity accumulated in the striatal region and the rate of increased utilization with time was calculated using a graphical method with back of the brain as a reference region. The rate constants for decarboxylation were 0.0070 ± 0.0007 (S. D) and 0.0121±0.0010min−1 for 5-hydroxy-L-(β-11C)tryptophan and L-(β-11 C)DOPA, respectively. After concomitant injection with unlabelled 5-hydroxy-L-tryptophan, the rate constant of 5-hydroxy-L-(β-11 C)tryptophan decreased dose-dependently and a 50 percent reduction was seen with a dose of about 4mg/kg of unlabelled compound. A decreased utilization rate of L-(β-11 C)DOPA was seen only after simultaneous injection of 30 mg/kg of either L-DOPA or 5-hydroxy-L-tryptophan. This capacity limitation was most likely interpreted as different affinity of the striatal aromatic amino acid decarboxylase for L-DOPA and 5-hydroxy-L-tryptophan, respectively.

L‐DOPA modulates striatal dopaminergic function in vivo: Evidence from PET investigations in nonhuman primates

Significant increases in striatal L‐[11C]DOPA retention were observed in adult female rhesus monkeys with positron emission tomography (PET) following administration of drugs that increase cerebral L‐DOPA concentrations. The monkeys were scanned twice: at baseline (using 10–50 μg of tracer substance) and during continuous administration of L‐DOPA (3 or 15 mg/kg/h) and 6‐R‐Erythro‐4,5,6,7‐tetrahydrobiopterin (6R‐BH4) (5 mg/kg/h) and during combined administration of both drugs. PET scans of L‐[11C]DOPA distribution were obtained in GE2048‐15B or GE4096‐15WB Plus positron tomographs. In all studies the specific striatal L‐[11C]DOPA influx rate increased by an average of 17–20%. These increases were significantly higher than the retest variability obtained with saline infusions under identical experimental conditions. In individual monkeys the magnitude of increase in the striatal L‐[11C]DOPA influx rate varied from no effect of the drug infusion to a 45% increase. Taken together, the results of this study demonstrate that L‐DOPA in itself can affect dopaminergic neurotransmission in vivo and also adds further evidence that the neuromodulatory effects of the amino acid are predominantly autoreceptor antagonist‐like. The findings most likely have importance for the further understanding of the dopaminergic system in neurodegenerative and psychiatric disorders. Synapse 25:56–61, 1997.

Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin and infusion of L-tyrosine on the in vivo L-[beta-11C] DOPA disposition in the monkey brain.

The effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) and L-tyrosine infusion on [11C]dopamine synthesis was analyzed in the striatum of Rhesus using positron emission tomography (PET). The rate for decarboxylation from L-[beta-11C]DOPA to [11C]dopamine was calculated using a graphical method with cerebellum as a reference region. Although the peripheral administration of 6R-BH4 at low dose (2 mg/kg) did not provide a significant increase in the rate of dopamine biosynthesis, a high dose of 6R-BH4 (20 mg/kg) induced an elevation of the rate. This 6R-BH4-induced elevation of the dopamine synthesis rate was further dose-dependently enhanced by the continuous infusion of L-tyrosine (0.2 and 1.0 mumol/min/kg). L-Tyrosine infusion with a rate of 1.0 mumol/min/kg caused an enhancement of the rate even during low dose administration of 6R-BH4 (2 mg/kg). L-Tyrosine infusion alone did not induce any elevation of the dopamine biosynthesis rate. The analysis of plasma indicated that the metabolic ratios of L-[beta-11C]DOPA to each metabolite were not affected by 6R-BH4 and/or L-tyrosine infusion. The results suggest that the low dose loading of tyrosine facilitates the activity of 6R-BH4 on the presynaptic dopamine biosynthesis, and also that the combined effects can be monitored by PET using L-[beta-11C]DOPA as a biochemical probe.

Liquid chromatographic analysis of brain homogenates and microdialysates for the quantification of L-[β-11C]DOPA and its metabolites for the validation of positron emission tomography studies

The clinical use of positron emission tomography, PET, with selected radiolabelled tracer molecules visualizing and quantitating physiological processes in the tissue relies in many situations on compartmental models for the interpretation of the radiosignal. Validation of such models must, therefore, include chromatographic analysis of the radioactivity composition of the signal. Rapid and sensitive liquid chromatographic methods amenable for automation for the analysis of [11C] labelled L-DOPA and its metabolites were therefore developed and validated for the quantitation of radioactivity composition in rat brain microdialysates as well as homogenates. Analysis included a simple isolation step, separation using reversed phase liquid chromatography with radiometric detection and permitted assay following tracer doses with an analysis time of 15 min. The analysis of radioactivity composition in the rat striatum showed that peripherally formed O-methyl L-DOPA constituted less than 20% of the radioactivity 40 min after injection of L-[beta-11C]DOPA. In the extracellular space the main component was [11C]-homovanillic acid which increased with time indicating rapid formation but slow elimination. The cumulation of radioactivity in the striatum corresponded to the radioactivity signal of dopamine and derived metabolites. The formation rate of dopamine in the rat corresponded closely to the utilization rate in the striatum of monkey and man measured with PET. This indicated that the rate constants measured with PET correlates well to the dopamine synthesis rate.

Determination of 5-hydroxy-l-[β-11C]tryptophan and its in vivo-formed radiolabeled metabolites in brain tissue using high performance liquid chromatography: A study supporting radiotracer kinetics obtained with positron emission tomography☆

A high performance liquid chromatographic system was developed for separation of 11C-labeled 5-hydroxy-L-tryptophan ([11C]HTP) and in vivo formed radiolabeled metabolites in rat brain tissue. Analysis of brain homogenate revealed that the main part of the radioactivity was associated with 11C-labeled 5-hydroxyindole-3-acetic acid after intravenous injection of [11C]HTP to the rat. The serotonin synthesis rate in the brain was calculated and closely correlated to the serotonin synthesis rate in monkey and human measured using positron emission tomography.